Pharmaceutically active benzoquinazoline compounds

ABSTRACT

Compounds of formula (I) or salts thereof, wherein the dotted Line represents a single or double bond, R 1  is alkyl or amino optionally substituted by alkyl, alkanoyl or benzyl group; R 2 , R 3 , R 4  and R 5  are the same or different and each is selected from hydrogen, phenyl, halo, nitro, a group S(O) n R 8  wherein n is the integer 0, 1 or 2 and R 8  is halo or alkyl or a group NR 9 R 10  wherein R 9  and R 10  are both hydrogen, a group NR 11 R 12  wherein R 11  and R 12  are the same or different and each is hydrogen or alkyl, a group OR 13  wherein R 13  is hydrogen or C 1-4  of alkyl optionally substituted by halo; a C 1-4  aliphatic group optionally substituted by a group OR 14  or NR 14 R 15  wherein R 14  and R 15  are the same or different and each is hydrogen or alkyl; or two of R 2  to R 5  are linked together to form a benzo group, or one of R 2  to R 5  is a group X—Y—R 16  wherein X is CH 2 , NR 17 , CO or S(O) m  and Y is CH 2 , NR 17 , O or S(O) m , or X—Y is O, NR 17 , —CH═CH— or N═N—, are disclosed as pharmacological agents useful in the treatment of tumours. Pharmaceutical compositions and methods for the preparation of compounds of formula (I) are also described.

This is a continuation of Ser. No. 09/588,790 filed Jun. 6, 2000 nowU.S. Pat. No. 6,306,865.

The present invention relates to novel benzoquinazoline thymidylatesynthase inhibitors, to processes for preparing them and pharmaceuticalformulations containing them. U.S. Pat. No. 4,814,335 discloses interalia that compounds of the formula (0):

wherein R is hydrogen, fluoro, nitro, optionally substituted amino,carboxy, azido, alkoxy, trimethylsulphonyl, trifluoromethylsulphonyl oralkoxycarbonyl have biological response-modifying activity, i.e.antiviral, antibacterial and anticancer activity. However, no specificexamples of compounds of the formula (0) are provided.

Thymidylate synthase is an enzyme catalysing the terminal step in the denovo synthesis of thymidylate required for DNA synthesis. It has beenpostulated that inhibitors of this enzyme may be expected to haveanti-tumour activity and it has been reported (Jones et al, J. Med.Chem. 1986, 29, 468) that the in-vivo antitumour activity ofN¹⁰-propargyl-5,8-dideazafolic acid arises solely from its inhibitoryeffect on this enzyme.

It has now been found that a group of benzoquinazoline compounds areinhibitors of the enzyme thymidylate synthase and have antitumouractivity.

Accordingly, the present invention provides compounds of the formula (I)

or a salt thereof, wherein the dotted line represents a single or doublebond,

R¹ is C₁₋₄ alkyl or amino optionally substituted by a C₁₋₄ alkyl, C₁₋₅alkanoyl or benzyl group;

R², R³, R⁴ and R⁵ are the same or different and each is selected fromhydrogen, phenyl, halo, nitro,

a group S(O)_(n)R⁸ wherein n is the integer 0, 1 or 2 and R⁸ is halo oris C₁₋₄ alkyl or a group NR⁹R¹⁰ wherein R⁹ and R¹⁰ are both hydrogen,

a group NR¹¹R¹² wherein R¹¹ and R¹² are the same or different and eachis hydrogen or C₁₋₄ alkyl,

a group OR¹³ wherein R¹³ is hydrogen or C₁₋₄ alkyl optionallysubstituted by halo;

a C₁₋₄ aliphatic group optionally substituted by a group OR¹⁴ or NR¹⁴R¹⁵wherein R¹⁴ and R¹⁵ are the same or different and each is hydrogen orC₁₋₄ alkyl;

or two of R² to R⁵ are linked together to form a benzo group,

or one of R² to R⁵ is a group —X—Y—R¹⁶ wherein X is CH₂, NR¹⁷, CO orS(O)_(m) and m is 0, 1 or 2 and R¹⁷ is hydrogen or a C₁₋₄ aliphaticgroup and Y is CH₂, NR^(17′), O, or S(O)_(m), wherein m′ is 0, 1 or 2and R^(17′) is hydrogen or a C₁₋₄ aliphatic group provided that X and Yare only the same when each is CH₂, or —X—Y— is a group —O—, —NR¹⁷—,—CH═CH— or —N═N— wherein R¹⁷ is as hereinbefore defined, R¹⁶ is a C₁₋₄aliphatic group or a 5- or 6-membered aromatic ring optionallysubstituted by a group R¹⁸ at a position at least one carbon atomremoved from that linked to Y, the 5- or 6-membered ring beingoptionally further substituted by a halo atom; and R¹⁸ is halo, C₁₋₄alkoxy, nitro, nitrile, C₁₋₄ alkyl optionally substituted by halo, haloor a group COR¹⁹ wherein R¹⁹ is hydroxy, C₁₋₄ alkoxy or C₁₋₆ alkyloptionally substituted by one or two carboxyl groups or C₁₋₁₂ estersthereof or R¹⁹ is a group NR²⁰R²¹ wherein R²⁰ and R²¹ are the same ordifferent and each is hydrogen or C₁₋₄ alkyl optionally substituted byhydroxy or R¹⁹ is an amino acid group or an ester thereof in which thefirst nitrogen atom of the amino acid group may be linked to the 5- or6-membered aromatic ring to form a further 5- or 6-membered heterocyclicring or R¹⁹ is an C₂₋₃ alkylene group linked to the 5- or 6-memberedaromatic ring to form a further 5- or 6-membered ring;

R⁶ and R⁷ are the same or different and each is C₁₋₄ alkyl optionallysubstituted by hydroxy or C₁₋₄ alkoxy or together form a benzo group;

provided that at least one of R² to R⁷ is other than hydrogen and thatR⁴ is not methoxy when R¹ is hydroxy or methyl.

By the term halo is meant fluoro, bromo, chloro and iodo.

By the term C₁₋₄ aliphatic group is meant a C₁₋₄ alkyl, alkenyl, oralkynyl group.

By the term amino acid group is meant naturally occurring amino acids.

Preferred amino acid groups include glycine, glutamic acid andpolyglutamic and groups.

When the amino acid group is linked to the 5- or 6-membered aromaticring, this is via a carbon atom of the aromatic ring adjacent to carbonto which COR¹⁹ is attached.

Preferably the dotted line is a double bond.

Suitable substituents for the aromatic ring R¹⁶ include halo, C₁₋₄ alkyland C₁₋₄ alkoxy each optionally substituted by one to five halo atoms.Most suitably there are one or two substituents selected from fluoro,chloro, methyl, trifluoromethyl and methoxy, and preferably fluoro, orno substituents on the aromatic ring. In one preferred embodiment,—X—Y—R¹⁶ is a group

wherein R¹⁸ is as hereinbefore defined and preferably a group COR¹⁹ ashereinbefore defined and R²² is hydrogen or fluoro.

In a further preferred embodiment X—Y—R¹⁶ is a group

wherein H₂NR^(19a) is a glutamic or polyglutamic acid group and Z isCH₂, S or O.

Suitably, R¹ is an amino group optionally substituted by one or twomethyl or ethyl groups or R¹ is a methyl or ethyl group. Preferably R¹is an amino or methyl group.

Suitably, at most only three, and preferably at most only two, of R² toR⁵ are other than hydrogen and each is independently selected fromhydrogen, halo, hydroxy, nitro, C₁₋₃ alkyl optionally substituted byhydroxy or C₁₋₂ alkoxy, C₁₋₃ alkoxy, amino optionally substituted by oneor two methyl or ethyl groups, or a group S(O)nR²³ wherein n is 0, 1 or2 and R²³ is a C₁₋₄ alkyl group or an amino group optionally substitutedby one or two methyl or ethyl groups, or one of R² to R⁵ is a group—X—Y—R²⁴ where R²⁴ is a group

wherein R¹⁸, R^(19a), R²² and Z are as hereinbefore defined. In onepreferred embodiment R¹⁸ is nitro or a group

wherein R²⁵, R²⁶ and R²⁷ are the same or different and each is hydrogenor a C₁₋₄ alkyl group and t is an integer from 0 to 6. Preferably R²⁵,R²⁶ and R²⁷ are hydrogen and t is 0. Preferably Z is CH₂ or S.

Preferably one of R² to R⁵ is a group —X—Y—R²⁴ as hereinbefore defined.Preferably R³ is a group —X—Y—R²⁴.

Suitably R⁶ and R⁷ are the same or different and each is hydrogen,methyl, ethyl or methyl substituted by bromo, hydroxy or methoxy.Preferably R⁷ is hydrogen and R⁶ is methyl.

Preferably —X—Y— is a group —SO₂NR¹⁷— or CH₂NR¹⁷ wherein R¹⁷ is ashereinbefore defined.

Suitably R¹⁷ is hydrogen or a C₁₋₄ alkyl or alkenyl group and preferablyR¹⁷ is hydrogen or methyl.

One group of compounds of the present invention is that of the formula(Ia)

or a salt thereof, wherein the dotted line represents a single or doublebond, R^(1a) is C₁₋₄ alkyl or amino optionally substituted by a C₁₋₄alkyl, C₁₋₅ alkanoyl or benzyl group; R^(2a), R^(3a), R^(4a) and R^(5a)are the same or different and each is selected from hydrogen, halo,nitro, a group S(O)_(n)R^(8a) wherein n is the integer 0, 1 or 2 andR^(8a) is halo or is a C₁₋₄ alkyl or amino group; a groupNR^(11a)R^(12a) wherein R^(1a) and R^(12a) are the same or different andeach is hydrogen or C₁₋₄ alkyl, a group OR^(13a) wherein R^(13a) ishydrogen or C₁₋₄ alkyl optionally substituted by halo, a C₁₋₄ aliphaticgroup optionally substituted by a group OR^(14a) or NR^(14a)R^(15a)wherein R^(14a) and R^(15a) are the same or different and each ishydrogen or C₁₋₄ alkyl, or one of R^(2a) to R^(5a) is a group —X—Y—Rwherein X is CH₂, NR^(17a), CO or S(O)_(m) and m is 0, 1 or 2 andR^(17a) is hydrogen or a C₁₋₄ aliphatic group and Y is CH₂, NR^(17′a),O, or S(O)_(m′) wherein m′ is 0, 1 or 2 and R^(17′a) is hydrogen or aC₁₋₄ aliphatic group provided that X and Y are only the same when eachis CH₂, or —X—Y— is a group —NR^(17a), —CH═CH— or —N═N— wherein R^(17a)is as hereinbefore defined, R^(16a) is a C₁₋₄ aliphatic group or anoptionally substituted 5- or 6-membered aromatic ring substituted by agroup R^(18a) at a position at least one carbon atom removed from thatlinked to Y and R^(18a) is nitro, nitrile, C₁₋₄ alkyl optionallysubstituted by halo, halo or a group COR^(19a) wherein R^(19a) is C₁₋₆alkyl optionally substituted by one or two carboxyl groups or C₁₋₄alkoxy, a group CONR^(20a)R^(21a) wherein R^(20a) and R^(21a) are thesame or different and each is hydrogen or C₁₋₄ alkyl or R^(19a) is aglutamic or polyglutamic acid group or an ester thereof in which thefirst nitrogen atom of the glutamic or polyglutamic acid group may belinked to the 5- or 6-membered aromatic ring to form a further 5- or6-membered heterocyclic ring; R^(6a) and R^(7a) are the same ordifferent and each is C₁₋₄ alkyl optionally substituted by hydroxy orC₁₋₄ alkoxy or together form a benzo group, provided that at least oneof R^(2a) to R^(7a) is other than hydrogen and that R^(4a) is notmethoxy when R^(1a) is hydroxy or methyl.

A further group of compounds of the present invention is that of theformula (II)

or a salt thereof, wherein R¹, R⁶, R⁷ and the dotted line are ashereinbefore defined and R²⁸ to R³¹ are the same or different and eachis selected from hydrogen, halo, nitro, a group S(O)_(n)R⁸, a groupNR¹¹R¹², a group OR¹³, or a C₁₋₄ aliphatic group optionally substitutedby a group OR¹⁴ or NR¹⁴R¹⁵ wherein R⁸, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ are ashereinbefore defined, provided that R²⁸ to R³¹ are not all hydrogen andthat R³⁰ is not methoxy wherein R¹ is hydroxy or methyl.

A preferred group of compounds of the present invention is that of theformula (III):

or a salt thereof, wherein R¹, R⁶ and R⁷ are as hereinbefore defined andR³² to R³⁵ are the same or different and one is a group X—Y—R¹⁶ and theothers are the same or different and each is selected from hydrogen,halo, nitro, a group S(O)_(n)R⁸, a group NR¹¹R¹², a group OR¹³ or a C₁₋₄aliphatic group optionally substituted by a group OR¹⁴ or NR¹⁴R¹⁵,wherein X, Y, R⁸, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are as hereinbeforedefined.

A further preferred group of compounds of the present invention is thatof the formula (IV):

wherein R¹, R⁶, R⁷ and R³² to R³² are as hereinbefore defined.

Preferably R³³ is a group X—Y—R¹⁶ as hereinbefore defined.

Preferred compounds of the formula (I) include:

3-Amino-9-bromobenzo[f]quinazolin-1(2H)-one

3-Amino-9-ethynylbenzo[f]quinazolin-1(2H)-one

N-(4-((3-Amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamicacid

N-(4-((1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)-sulfonamido)benzoyl)-L-glutamicacid

N-(4-((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)-benzoyl)-L-glutamicacid

N-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)-L-glutamicacid

N-(4(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glumaticacid

(S)-2-(5-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)-amino-1-oxo-2-isoindolinyl)glutamicacid

9-((4-Acetylanilino)methyl)-3-methylbenzo[f]quinazolin-1(2H)-one

3-Methyl-9-((4-nitroanilino)methyl)benzo[f]quinazolin-1(2H)-one

N-(4-(((3-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamicacid

3-Amino-9-((4-nitroanilino)methyl)benzo[f]quinazolin-1(2H)-one

9-((4-Acetylanilino)methyl)-3-aminobenzo[f]quinazolin-1(2H)-one

(RS)-2-(2-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)phenyl)-2-oxoethyl)glutaricacid

Ethyl-4-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)phenyl)-4-oxobutyrate

4-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)phenyl)-4-oxobutyricacid

N-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)glycine

EthylN-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)glycinate

Certain compounds of the formula (I) contain asymmetric carbon atoms andare, therefore, capable of existing as optical isomers. The individualisomers and mixtures of these are included within the scope of thepresent invention.

Salts of the compounds of the present invention may comprise acidaddition salts derived from an amino group or anionic species derivedfrom a compound of formula (I), for example when this is substituted bya carboxy group, and a cation. In both types of salts, the therapeuticactivity resides in the moiety derived from the compound of theinvention as defined herein and the identity of the other component isof less importance although for therapeutic and prophylactic purposes itis, preferably, pharmaceutically acceptable to the patient. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom mineral acids, such as hydrochloric, hydrobromic, phosphoric,metaphosphoric, nitric and sulphuric acids, and organic acids, such astartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric,benzoic, glycollic, gluconic, succinic and methanesulphonic andarylsulphonic, for example p-toluenesulphonic, acids. Examples of saltscomprising an anionic species derived from a compound of formula (I) anda cation include ammonium salts, alkali metal salts, such as sodium andpotassium salts, alkaline earth salts, such as magnesium and calciumsalts, and salts formed with organic bases, for example, amino saltsderived from mono-, di- or tri-(lower alkyl) or (lower alkanol)amines,such as triethanolamine and diethylamino-ethylamine, and salts withheterocyclic amines such as piperidine, pyridine, piperazine andmorpholine. The pharmaceutically acceptable salts together with thesalts which are not thus acceptable have utility in the isolation and/orthe purification of the compounds of the invention, and thepharmaceutically unacceptable salts are also useful in being convertibleto the pharmaceutically acceptable salts by techniques well known in theart.

Esters of compounds of the formula (I), formed from compounds of theformula (I) which contain a carboxy group are often useful intermediatesin the preparation of the parent acid.

The present invention also provides a process for the preparation ofcompounds of the formula (I) which comprises a method well known tothose skilled in the art, for example:

(i) when it is required to prepare a compound of the formula (I) whereinthe dotted line represents a single bond, the reaction of a compound ofthe formula (V)

wherein R² to R⁵ are as hereinbefore defined and R³⁶ is a C₁₋₄ alkylgroup, with a compound

wherein R¹ is as hereinbefore defined. This reaction is suitably carriedout in a polar solvent, for example a C₁₋₄ alkanol or glycol,conveniently methanol or ethanol, normally in the presence of a base,for example a metal alkoxide conveniently formed from the metal and thesolvent, i.e. sodium methoxide or ethoxide, at an elevated temperature,for example 50° to 150° C. and conveniently 60° to 90° C. The compoundof the formula

is conveniently liberated in situ from a salt form, for example thehydrochloride or carbonate salt, by the base which is preferably presentin the reaction mixture. This reaction is a preferred method forpreparing those compounds of the formula (I) wherein one of R² to R⁵ isnot a group XYR¹⁶.

(ii) the direct insertion of a substituent R², R³, R⁴ or R⁵ into thearomatic ring system. This is particularly suitable for the insertion ofhalo or nitro substituents or a group SO₂hal. This is carried out bymethods conventionally employed to insert these substituents on aromaticring systems, for example in the case of a bromo substituent: reactionof the corresponding compound where R² to R⁷ are all hydrogen withbromine in a suitable solvent such as glacial acetic acid at atemperature between 20° and 100° C., conveniently between 50° and 70°C.; in the case of a substituent SO₂hal: reaction of the correspondingcompound where R² to R⁷ are all hydrogen with a halosulphonic acid at atemperature between −5° and 100° C., conveniently between 20° and 30°C.; in the case of a nitro substituent: reaction of the correspondingcompound where R² to R⁷ are hydrogen with nitric acid or potassiumnitrate in sulphuric acid at −30° to 50° C. and conveniently at −5° to5° C. The position of attachment of the substituent to the aromatic ringsystem may be effected by, inter alia, the nature of the substituent R¹.Thus, when R¹ is an amino group an SO₂ group will be attached to the8-position but when R¹ is a methyl group an SO₂ group will be attachedto the 9-position.

(iii) the hydrolysis of a compound of the formula (VI)

wherein R¹ to R⁷ are as hereinbefore defined. This hydrolysis isconveniently carried out by acid, for example a mineral acid such ashydrochloric acid, at a temperature of between 20° and 120° C. andconveniently at between 60° and 100° C.

(iv) the conversion of one compound of the formula (I) to a furthercompound of the formula (I), for example:

(a) the dehydrogenation of a compound of the formula (VII):

wherein R¹ to R⁷ are as hereinbefore defined and R³⁷ is C₁₋₄ alkyl or aprimary, secondary or tertiary amino group within the definition of R¹or when it is desired to prepare a compound of the formula (I) whereinR¹ is a primary amino or a hydroxy group R³⁷ is a protected amino orhydroxy group; and thereafter removing the protecting group whereappropriate. This dehydrogenation is conveniently carried out by (i)bromination of the 5- or 6-position of the compound of the formula (VII)by a reagent such as N-bromosuccinimide followed by dehydrobromination(ii) catalytic dehydrogenation in inert solvent (e.g. diglyme), (iii)dehydrogenation with DDQ. Reaction (i) is conveniently carried out inthe presence of a base, such as pyridine, in a inert solvent, forexample benzene, at a non-extreme temperature, for example between 0 and80° C. The pivaloyl group is a suitable protecting group when R¹ is NH₂.

The compounds of the formula (VII) are conveniently prepared from thecorresponding compounds of the formula (V) as described in method (i)above.

(b) when it is desired to prepare a compound of the formula (I) whereinone of R² to R⁵ is a group S(O)_(m)YR¹⁶ wherein Y and R¹⁶ are ashereinbefore defined, the reaction of the analogous precursorsubstituted by the group SO₂hal with a compound HYR¹⁶ wherein hal ishalo and R¹⁶ is as hereinbefore defined. Suitably this reaction iscarried out in a basic medium, for example pyridine, at an elevatedtemperature, i.e. 25 to 175° C. The precursor is prepared by analogy tomethod (ii) above whereby a compound of formula (I) or (II), wherein atleast one of R²-R⁵ is H in the position desired for substitution, isreacted with chlorosulfonic acid at −5 to 100° C.

(c) when it is desired to prepare a compound of the formula (I)substituted by an amino group the reduction of the correspondingcompound substituted by a nitro group. Reduction is suitably carried outby hydrogenation in the presence of a transition metal catalyst forexample palladium on charcoal in an inert solvent, for example analkanol, such as ethanol, at a non-extreme temperature, for example (25to 35° C.).

(d) when it is desired to prepare a compound of the formula (I)substituted by a hydroxy group, the removal of an alkyl group from thecorresponding alkoxy compound. This reaction is conveniently carried outin the presence of a strong acid, such as hydrobromic acid at anon-extreme temperature.

(e) when there is more than one substituent R² to R⁵, removal of one ofthe substituents, for example removal of bromine by catalyticdebromination, such as hydrogenation in the presence of a transitionmetal catalyst, conveniently palladium on charcoal, in a polar solventsuch as a C₁₋₄ alkanol at between 0° and 50° C. conveniently 20° to 30°C.

(f) when one of R² to R⁵ is an alkyl group, the halogenation of thisalkyl group, for example bromination by N-bromo-succinimide in an inertsolvent, such as benzene, at a temperature between 20° and 120° C.,conveniently 70° to 90° C.

(g) the displacement of a leaving group from a substituent R² to R⁵ byanother group, for example conversion of a haloalkyl group to anhydroxyalkyl or alkoxyalkyl group by reaction with an alkali metalhydroxide or alkoxide respectively in alkanol, at a temperature between20° and 120° C.; or conversion of a group CH₂hal wherein hal is halo toa group CH₂YR¹⁶ by reaction with a compound HYR¹⁶ wherein Y and R¹⁶ areas hereinbefore defined, for example N-(4-aminobenzoyl)-L-glutamic aciddiethyl ester, ethyl N-(4-amino-2-fluorobenzoyl)glycinate or4-fluoroanilino, in a dipolar aprotic solvent, such asdimethylformamide, at a non-extreme temperature, for example 25° to 160°C. and conveniently 95° to 105° C. optionally followed by the additionof a weak base such as sodium or patassium carbonate or bicarbonate.

(h) the replacement of one substituent R² to R⁵ by another substituentR² to R⁵, for example displacement of bromo by an alkynyl moiety whichis preferably protected by a trialkylsilyl group in the presence of asuitable catalyst, such as palladium acetate. The trialkylsilyl groupmay then be removed by base catalysed hydrolysis, for example withpotassium carbonate. The alkynyl group can be reduced, by catalytichydrogenation, to an alkenyl or alkyl group.

When R¹ is an amino group, it is often convenient to carry out theseconversions with the amino group protected, for example with a pivaloylgroup.

The compounds of the formula (V) may be prepared by the reaction of adialkyl carbonate with a compound of the formula (VIII)

wherein R² to R⁵ are as hereinbefore defined in the presence of a base,conveniently sodium hydride. This reaction is analogous to thatdescribed by J. Vebrel and R. Carrie (Bull. Soc. Chim. Fr., 1982, 161).

The compounds of the formula (VI) wherein R¹=NH₂ may be prepared by thereaction of dicyandiamide with a compound of the formula (VIII). Thisreaction is described by Rosowsky et al (J. Heterocyclic Chem. 9, 263(1972).

The compounds of the formula (VIII) may be prepared by methods wellknown to those skilled in the art, for example by methods analogous tothose described by J. Vebrel and R. Carrie (Bull. Soc. Chim. Fr., 1982,161) and J. H. Burkhalter and J. R. Campbell (J. Org. Chem., 26, 4332(1961) and those outlined in Schemes 1, 2 and 3 appended hereto.

The present invention also relates to novel chemical intermediates ofthe formula (VI). Compounds of the formula (VI) possess pharmocologicalproperties and may therefore be useful in their own right as well asbeing useful intermediates in the preparation of compounds of theformula (I).

Whilst it is possible for the compounds or salts of the presentinvention to be administered as the raw chemical, it is preferred topresent them in the form of a pharmaceutical formulation. Accordingly,the present invention further provides a pharmaceutical formulation, formedicinal application, which comprises a compound of the presentinvention or a pharmaceutically acceptable salt thereof, as hereinbeforedefined, and a pharmaceutically acceptable carrier therefor.

The pharmaceutical formulation may optionally contain other therapeuticagents that may usefully be employed in conjunction with the compound orsalt of the present invention, for example a pyrimidine nucleosidetransport inhibitor that is capable of enhancing the antineoplasticactivity of the compounds and salts of the present invention. Theexpression “pharmaceutically acceptable” as used herein in relation tothe carrier is used in the sense of being compatible with the compoundor salt of the invention employed in the formulation and with any othertherapeutic agent that may be present, and not being detrimental to therecipient thereof. The carrier itself may constitute one or moreexcipients conventionally used in the art of pharmacy that enable thecompound or salt of the present invention and any other therapeuticagent that may be present, to be formulated as a pharmaceuticalformulation.

The pharmaceutical formulations of the present invention include thosesuitable for oral, parenteral (including subcutaneous, intradermal,intramuscular and intravenous) and rectal administration although themost suitable route will probably depend upon, for example, thecondition and identity of the recipient. The formulations mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. All methods includethe step of bringing into association the active ingredient, i.e., thecompound or salt of the present invention, with the carrier. In general,the formulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with a liquid carrier or, a finelydivided solid carrier or both, and then, if necessary, forming theassociated mixture into the desired formulation.

The pharmaceutical formulations of the present invention suitable fororal administration may be presented as discrete units, such as acapsule, cachet, tablet, or lozenge, each containing a predeterminedamount of the active ingredient; as a powder or granules; as a solutionor a suspension in an aqueous liquid or a non-aqueous liquid such as asyrup, elixir or a draught, or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The formulation may also be a bolus,electuary or paste.

Generally, a tablet is the most convenient pharmaceutical formulationsuitable for oral administration. A tablet may be made by compressing ormoulding the active ingredient with the pharmaceutically acceptablecarrier. Compressed tablets may be prepared by compressing in a suitablemachine the active ingredient in a free-flowing form, such as a powderor granules, in admixture with, for example, a binding agent, an inertdiluent, a lubricating agent, a disintegrating agent and/or a surfaceactive agent. Moulded tablets may be prepared by moulding in a suitablemachine a mixture of the powdered active ingredient moistened with aninert liquid diluent. The tablets may optionally be coated or scored andmay be formulated so as to provide slow or controlled release of theactive ingredient.

The pharmaceutical formulations of the present invention suitable forparenteral administration include aqueous and non-aqueous sterileinjection solutions which may contain, for example, an anti-oxidant, abuffer, a bacteriostat and a solution which renders the compositionisotonic with the blood of the recipient, and aqueous and non-aqueoussterile suspensions which may contain, for example, a suspending agentand a thickening agent. The formulations may be presented in uni-dose ormulti-dose containers, for example sealed ampoules and vials, and may bestored in a freeze-dried (lyophilized) condition requiring only theaddition of the sterile liquid carrier, for example water for injection,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

The pharmaceutical formulations of the present invention suitable forrectal administration may be presented as a suppository containing, forexample, cocoa butter and polyethylene glycol.

As mentioned hereinbefore, compounds and salts of formula (I) haveanti-neoplastic activity as demonstrated hereinafter in the human colonSW480 adenocarcinoma cell culture cytotoxicity tests in whichrepresentative compounds of the present invention have been shown to beactive. Compounds and salts of formula (I) also have anti-neoplasticactivity as determined hereinafter in the human breast MCF7adenocarcinoma cell culture cytotoxicity tests. It has thus beenestablished that compounds of the present invention are able to inhibitneoplastic growth. Therefore, compounds and salts of the presentinvention are of use in medicine and in particular in the treatment ofneoplastic growth, including solid tumours such as melanoma, breast andcolon tumours in mammals. Accordingly, the present invention yet furtherprovides a method for the treatment of susceptible malignant tumours andleukemia in an animal, e.g., a mammal, which comprises administering tothe animal a therapeutically effective amount of a compound or salt ofthe present invention. In the alternative, there is also provided acompound or salt of the present invention for use in medicine and inparticular for use in the treatment of a neoplastic growth, e.g.,malignant tumours.

The present invention also provides the use of a compound of formula (I)or a salt thereof for the manufacture of a medicament for the treatmentof neoplastic growth.

The animal requiring treatment with a compound or salt of the presentinvention is usually a mammal, such as a human being.

Particular examples of a neoplastic growth requiring treatment includemalignant tumours.

Compounds and salts of the formula (I) also inhibit the enzymeThymidylate Synthase from E. coli and Candida Albicans. Therefore,compounds and salts of the present invention may be of use in thetreatment of bacterial and fungal infections in mammals.

The route by which the compound or salt of the present invention isadministered to the animal may be oral, topical, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous or rectal). If thecompound or salt is presented in the form of a pharmaceuticalformulation, which, as mentioned hereinbefore, is preferred, then theactual formulation employed will of course depend on the route ofadministration elected by the physician or veterinarian. For example, iforal administration is preferred, then the pharmaceutical formulationemployed is, preferably, one which is suitable for such a route.

A therapeutically effective amount of a compound or salt of the presentinvention will depend upon a number of factors including, for example,the age and weight of the animal, the precise condition requiringtreatment and its severity, the nature of the formulation, and the routeof administration, and will ultimately be at the discretion of theattendant physician or veterinarian. However, an effective amount of acompound of the present invention for the treatment of neoplasticgrowth, for example colon or breast carcinoma will generally be in therange of 0.1 to 100 mg/kg body weight of recipient (mammal) per day andmore usually in the range of 1 to 10 mg/kg body weight per day. Thus,for a 70 kg adult mammal, the actual amount per day would usually befrom 70 to 700 mg and this amount may be given in a single dose per dayor more usually in a number (such as two, three, four, five or six) ofsub-doses per day such that the total daily dose is the same. Aneffective amount of a salt of the present invention may be determined asa proportion of the effective amount of the compound par se.

An effective amount of a compound of the present invention for thetreatment of disorders of the immune system (e.g. rheumatoid arthritisand tissue rejection) and related diseases such as psoriasis, willgenerally be in the range of 0.07-10 mg/kg body weight of recipient(mammal) per day. Thus for a 70 kg adult human, the actual amount perday would usually be from about 5-700 mg per day and this amount may begiven in a single dose per day, or more usually dosing would beintermittent e.g. at 12 hourly intervals or weekly. An effective amountof a salt of the present invention may be determined as a proportion ofthe effective amount of the compound per se.

The treatment of neoplastic growth with a compound of the presentinvention may at times require the administration to the animal of anantidote or rescue agent, e.g. thymidine.

The following examples illustrate the preparation of compounds of thepresent invention, their pharmacological properties and formulationscontaining them.

EXAMPLE A

Alkyl 3,4-dihydro-2-hydroxy-1-naphthoates were prepared by reaction ofsodium enolates of the starting 2-tetralones with dimethyl or diethylcarbonate in the presence or absence or a co-solvent such as toluene.For example,

Methyl 7-bromo-3,4-dihydro-2-hydroxy-1-naphthoate

To a refluxing stirred suspension of sodium hydride (5.6 g of 80% inoil, 187 mmoles) in dry dimethyl carbonate (120 ml) under a nitrogenatmosphere was added a solution of 7-bromo-2-tetralone (14 g, 61 mmoles)in dry dimethyl carbonate (60 ml) dropwise over 40 minutes. Refluxingwas continued for an additional 45 minutes and then cooled to roomtemperature. The reaction was carefully quenched with glacial aceticacid, diluted with one volume of water and extracted with ethyl acetate(150 ml). The organic phase was dried over magnesium sulfate, filteredand evaporated under reduced pressure to leave a residue which waspurified using silica gel column chromatography eluting with ethylacetate:hexane (39:7) to give methyl7-bromo-3,4-dihydro-2-hydroxy-1-naphthoate as a white solid. (15.2 g,86%).

The following 3,4-dihydro-2-hydroxy-1-naphthoates were prepared usingthe procedure described above without significant modification: methyl,ethyl 4-methyl, methyl 5-fluoro, ethyl 5-chloro, methyl 5-bromo, ethyl5-iodo, ethyl-5-methyl-, ethyl 5-phenyl-, ethyl 6-fluoro-, ethyl6-chloro-, ethyl 6-bromo-, ethyl 7-fluoro, ethyl 7-chloro, ethyl7-bromo-, ethyl 7-iodo-, ethyl-7-methyl-, ethyl 7-phenyl-, methyl7-ethoxy-, methyl 7-methylthio-, methyl 7-ethylthio-, ethyl 8-chloro-,ethyl-4,4-dimethyl-, ethyl-5,7-dimethyl-, ethyl 6,7-dichloro-, ethyl6,7-dimethoxy-, ethyl 6-chloro-4-methyl-, and ethyl7-chloro-3,4-dihydro-2-hydroxy-4-methyl-1-naphthoate.

The following 2-tetralones were obtained from commercial suppliers2-tetralone; 5-methoxy-2-tetralone; 6-methoxy-2-tetralone;7-methoxy-2-tetralone; and 6,7-dimethoxy-2-tetralone.

Other 2-tetralones were obtained by one or two methods A) from thecorresponding 1-tetralones by a four-step carbonyl transpositionsequence¹, or B) from appropriately substituted phenylacetic acids bycyclization of the corresponding acid chlorides with ethylene orpropylene under Friedel-Crafts conditions². For example:

Method A 4,4-Dimethyl-2-tetralone

To a stirred suspension of sodium borohydride (3.5 g, 93 mmoles) in drymethanol (50 ml) at 0° C. under a nitrogen atmosphere was added asolution of 4,4-dimethyl-1-tetralone (10 g, 57.4 mmoles) in drymethanol:toluene (1:3) dropwise over a 45 minute period. After this timethe mixture was allowed to warm to room temperature, and then twovolumes of water were added. After stirring for 1 hour, the organiclayer was separated, dried over magnesium sulfate, filtered, andevaporated under reduced pressure to leave a light yellow oil. This waspurified by silica gel column chromatrography eluting with ethylacetate:hexane (1:9) to give 1,2,3,4-tetrahydro-4,4-dimethyl-1-naphtholas a colorless oil. (9.89 g, 98%).

A mixture of 1,2,3,4-tetrahydro-4,4-dimethyl-1-naphthol (9.6 g, 54.5mmoles) in 20% aqueous oxalic acid was stirred and heated to reflux for5 hours. After cooling, the reaction mixture was diluted with one volumeof water and then extracted with one volume of ether. The aqueous layerwas extracted again with one volume of ethyl acetate and the combinedorganic phases were dried over magnesium sulfate, filtered, andevaporated under reduced pressure to leave an oil which was purifiedusing silica gel column chromatography, eluting with ethylacetate:hexane (0.1:49.9) to give 1,2-dihydro-1,1-dimethylnaphthalene asa colorless oil. (4.76 g, 55%).

To a stirred mixture of 30% hydrogen peroxide (5 ml) and 97% formic acid(20 ml) in a round bottom flask equipped with an additional funnel,thermometer, and an ice water bath was added1,2-dihydro-1,1-dimethylnaphthalene (4.5 g, 28 mmoles) dropwise at 5° C.under a nitrogen atmosphere. When the addition was complete, thereaction vessel was raised above the cooling bath to allow the reactiontemperature to rise to just between 35° C. at which point the flask wasimmersed again. In this manner the temperature of the reaction wasmaintained between 30 and 35° C. for 45 minutes. After this time theexothermic phase of the reaction ended and the mixture was allowed tocool to room temperature. A solution of 10% aqueous ferric sulfate wasadded in portions of a few milliliters each until cloudiness persistedin the stirred mixture and then all solvent was removed under reducedpressure. The viscous brown residue was refluxed with 20% H₂SO₄ (20 ml)for 4 hours and then cooled, extracted three times with ether (75 mleach), dried over magnesium sulfate, filtered and evaporated to leave abrown oil. This was purified using silica gel column chromatographyeluting with ethyl acetate:hexane (7:93) to give4,4-dimethyl-2-tetralone. (3.4 g, 74%). Overall yield=40%.

Using method A, 4-methyl-2-tetralone and 5,7-dimethyl-2-tetralone werealso prepared.

Method B 6-Bromo-2-tetralone

A mixture of oxalyl chloride (10 g) and 4-bromophenylacetic acid³ (25 g,11.6 mmoles) was stirred under a nitrogen atmosphere at room temperaturefor 2 hours and then refluxed for 4 hours more. After cooling, theexcess oxalyl chloride was removed by evaporation under reduced pressureto give crude 4-bromophenylacetyl chloride as a light yellow oil whichwas not purified further.

To a two-liter round bottom flask equipped with a gas inlet tubeconnected to an external tank of ethylene, an addition funnel containinga solution of the crude 4-bromophenylacetyl chloride described above inmethylene chloride (75 ml), a thermometer, a gas inlet adapter connectedto a bubbler and a positive nitrogen flow, and a heavy-duty magneticstirrer was added dry methylene chloride (1000 ml) and aluminum chloride(56 g, 0.42 mole). The stirred suspension was cooled to −10° C. using anice/salt bath, and ethylene was introduced through the gas inlet tube,which was positioned just above the vortex. Dropwise addition of thephenylacetyl chloride solution was started at a moderate rate, andadjusted periodically so that the reaction temperature stayed below 0°C. Ethylene flow was continued for 30 minutes after addition of the acidchloride solution was complete, and then reaction mixture was pouredover 2000 ml of ice, stirred vigorously for a few minutes, and left tosit until the ice melted. The methylene chloride layer was separated andthe aqueous layer was extracted three times with methylene chloride (100ml each). Combined methylene chloride layers were filtered through ashort silica gel plug and then evaporated under reduced pressure toleave an amber-colored oil, which was purified using silica gel columnchromatrography, eluting with ethyl acetate:hexane (35:65) to give6-bromo-2-tetralone as an amber crystalline solid. (25 g, 95%).

The following 2-tetralones were also prepared using method B 5-fluoro-,5-chloro-, 5-bromo-, 5-iodo-, 5-methyl-, 5-phenyl-, 6-fluoro-,6-chloro-, 7-fluoro-, 7-chloro-, 7-bromo-, 7-iodo-, 7-methyl-,7-phenyl-, 7-ethoxy-, 7-methylthio-, 7-ethylthio-, 8-chloro-,6,7-dichloro-, 6-chloro-4-methyl-, and 7-chloro-4-methyl-2-tetralone.

1. J. Vebrel and R. Carrie, Bull. Soc. Chim. Fr.,

2. J. H. Burkhalter and J. R. Campbell, J. Org. Chem., 26, 4932, 1961.

3. 3-substituted phenylacetic acids led to mixtures of 5- and7-substituted 2-tetralones which were separable by silica gel columnchromatography or recrystallization from ether:hexane or ethylacetate:hexane solvent mixtures.

The phenylacetic acids required for the syntheses of the 2-tetraloneswere generally commercially available. The following exceptions(3-ethoxy-, 3-ethylthio-, 3-methylthio- and 3-phenylphenylacetic acids)were synthesized as indicated below.

3-Ethoxyphenylacetic acid

A. Methyl 3-ethoxyphenylacetate

Methyl 3-hydroxyphenylacetate (132.5 g, 0.80 mole) was added dropwise toa suspension of 50% NaH (43.2 g, 0.90 mole) in DMF (ie) at 0° C. underN₂. The solution was stirred 1 hour at room temperature, cooled in anice bath, and ethyl bromide (120 ml, 1.6 mole) added. The reactionmixture was stirred overnight at room temperature, filtered, andconcentrated in vacuo. A solution of the residue in diethyl ether waswashed with dilute NaOH solution and saturated NaCl, dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by chromatography onsilica gel eluting with ethyl acetate:hexane (1:39→1:9) to give methyl3-ethoxyphenylacetate (94.9 g). ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.30 (t,J=7 Hz, 3H, ethylCH₃), 3.59 (s, 3H, esterCH₃), 3.61 (s, 2H, ArCH₂), 3.98(q, J=7 Hz, 2H, ethylCH₂), 6.78-6.81 (m, 3H), 7.16-7.24 (m, 1H).

B. 3-Ethoxyohenylacetic acid

A solution of methyl 3-ethoxyphenylacetate (92.6 g, 0.4 mole) inmethanol (600 ml) and 6.25 N NaOH (400 ml) was stirred overnight at roomtemperature and then filtered and concentrated in vacuo to remove themethanol. The solution was adjusted to pH 1 with concentrated HCl, theresulting precipitate filtered, washed with ice water, and dried underhigh vacuum to give 3-ethoxyphenyl acetic acid (74.5 g). M.p=89-90° C.¹H NMR (DMSO-d₆, 200 MHz) δ: 1.30 (6, J=7 Hz, 3H, CH₃), 3.50 (s, 2H,ArCH₂), 3.98 (q, J=7 Hz, 2H, ethylCH₂), 6.75-6.80 (m, 3H, Ar), 7.14-7.23(m, 1H, Ar). (Lit. ref.: J. Med. Chem, 1980, 23(4) 437-444.

2-(3-Biphenylyl)acetic acid

A. 2-(3-Biphenylyl)ethanol

To a solution of 3-bromobiphenyl (18 g, 77 mmol) in diethyl ether (150ml) under N₂ cooled to −78° C. was added 1.6 M t-butyl lithium inpentane (100 ml, 0.16 mole) via cannula over a 15 minute period. Thesolution was stirred 30 minutes at −78° C., ethylene oxide (9 g, 0.2mole added and the reaction mixture allowed to warm to room temperatureover a 1 hour period. The solution was boiled briefly to drive offexcess ethylene oxide, transferred to a separatory funnel, a smallvolume of water added, and neutralized with concentrated HCl. Theorganic solution was dried (MgSO₄), concentrated in vacuo and theresidue purified by chromatography on silica gel eluting with ethylacetate:hexane (1:4) to give 2-(3-biphenylyl)ethanol (10.5 g). ¹H NMR(CDCl₃, 60 MHz) δ: 2.81 (t, J=7 Hz, 2H, CH₂), 3.76 (t, J=7 Hz, 2H, CH₂),6.95-7.70 (m, 9H, Ar).

B. 2-(3-Biphenylyl)acetic acid

To a stirred solution of 2-(3′-biphenyl)ethanol (10.5 g, 53.0 mmol) inacetone (100 ml) at 0° C. was added 3N chromium trioxide in dilutesulphuric acid (^(˜)20 ml) portion wise over a 30 minute period untilthe orange color persisted. The mixture was stirred for 20 minutes,ethanol added to destroy the excess of oxidant and the solutionconcentrated in vacuo. The residue was taken up in ethyl acetate-diethylether (250 ml), washed with water and saturated brine, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by chromatography onsilica gel eluting with ethyl acetate:hexane (2:3) to give2-(3-biphenylyl)acetic acid (3.35 g). ¹H NMR (CDCl₃, 60 MHz) δ: 3.61 (s,2H, CH₂), 7.00-7.65 (m, 9H, Ar).

3-Ethylthiophenylacetic acid

To a solution of methyl 3-aminophenylacetate (102 g, 0.62 mole) in 1NHCl (1600 ml) cooled in an ice bath was added NaNO₂ (42.7 g, 0.62 mole)portionwise and the solution stirred for 20 minutes. A solution ofpotassium ethanethiolate was prepared by adding ethanethiol (202 ml,2.73 mole) dropwise over 10 minutes to a solution of 87.5% KOH (159 g,2.48 mole) in water (1.2 l) at 0° C. The diazonium salt solution wasthen added via cannula to the solution of potassium ethanethiolate andthe reaction mixture was stirred 30 minutes in an ice bath. Diethylether (^(˜)1.5 l) was added and the mixture was stirred 1.5 hours atroom temperature. The ether layer was separated, the aqueous phasefurther extracted with diethyl ether (3×700 ml), and the combined ethersolutions concentrated. The residue was eluted from silica gel withethyl acetate:hexane (1:19) to give a mixture of methyl3-ethylthiophenylacetate ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.21 (t, J=7 Hz,3H, ethylCH₃), 2.95 CH₂), 3.60 (s, 3H, OCH₃), 3.65 (s, 2H, ArCH₂),7.02-7.44 (m, Ar), and methyl phenylacetate (85.9 g). The esters (84 g)were hydrolyzed in a solution of methanol (500 ml) and 6.25 N NaOH (100ml) stirred overnight at room temperature. The solution was concentratedin vacuo to remove the methanol, the remaining solution acidified withconcentrated HCl and the resulting solid was extracted into diethylether. The ether solution was washed with brine (3×100 ml), dried(Na₂SO₄) and concentrated. Vacuum distillation (0.5 mm Hg) gave adistillate (100-115° C.) of phenylacetic acid and a residue of3-ethylthiophenylacetic acid. The residue in the flask solidified uponcooling to give 3-ethylthiophenylacetic acid (49.8 g). Mp=49-51° C. ¹HNMR (DMSO-d₆, 200 MHz) δ: 1.21 (t, J=7 Hz, 3H, CH₃), 2.95 (q, J=7 Hz,2H, SCH₂), 3.54 (s, 2H, ArCH), 7.01-7.28 (m, 4H, Ar), 12.33 (br s, 1H,CO₂H). Mass spectrum (CI-CH₄): 197 (M+1, 100%).

3-Methylthiophenylacetic acid

Prepared in an essentially similar fashion from methyl3-aminophenyl-acetate (11 g, 0.67 mole) and potassium methanethiolate(2.68 mole) to give 3-methylthiophenylacetic acid (21.0 g). Mp=76-77°C., ¹H NMR (DMSO-d₆, 200 MHz) δ: 2.44 (s, 3H, SCH₃), 3.53 (s, 2H,ArCH₂), 7.02-7.28 (m, 4H, Ar), 12.30 (br s, 1H, CO₂H). Mass spectrum(CI-CH₄): 183 (M+1, 100%). (Lit. ref.: Plant Physiol 42(11) 2596-1600(1967).

The intermediate 7-ethynyl-2-tetralone for the synthesis of3-amino-5,6-dihydro-9-ethynylbenzo[f]quinazolin-1(2H)-one wassynthesized as described below.

7-Ethynyl-2-tetralone

A. 7′-Bromo-3′,4′-dihydrospiro[1,3-dioxolane-2,2′(1′H)-naphthalene]

A solution of 7-bromo-2-tetralone (1.1 g, 4.9 mmol), ethylene glycol(0.62 g, 10 mmol), and p-toluensulfonic acid (80 mg, 0.42 mmol) inbenzene (20 ml) was stirred under N₂ at reflux utilizing a Dean-Starktrap for 45 minutes. The cooled solution was diluted with diethyl ether(60 ml), washed with saturated NaHCO₃ solution (2×10 ml), dried (MgSO₄)and concentrated in vacuo to give7′-bromo-3′,4′-dihydrospiro[1,3-dioxolane-2,2′(1′H)-naphthalene] as anoil (1.2 g). ¹H NMR (CDCl₃, 200 MHz) δ: 1.95 (t, J=7 Hz, 2H, CH₂), 2.91(t, J=7 Hz, 2H, CH₂), 2.95 (s, 2H, CH₂), 4.01 (s, 4H, OCH₂CH₂O), 6.97(d, J=8 Hz, 1H, Ar), 7.15-7.27 (m, 2H, Ar).

B.3′4′-Dihydro-7′-[2-trimethylsilyl)ethynyl]spiro[1,3-dioxolane-2,2′(1′H)-naphthalene]

A solution of7′-bromo-3′,4′-dihydrospiro[1,3-dioxolane-2,2′(1H)-naphthalene] (3.40 g,12.6 mmol), trimethylsilylacetylene (7.0 ml, 50 mmol) (Aldrich),triphenylphosphine (0.66 g, 2.50 mmol), and palladium acetate (0.28 g,1.25 mmol) in triethylamine (18 ml) was stirred at 70° C. for 18 hoursand then concentrated in vacuo. The residue was absorbed onto silica gelfrom a diethyl ether solution and partially purified by elution throughsilica gel (15 g) with diethyl ether:hexane (1:9). Further purificationby chromatography on silica gel eluting with ethyl acetate:hexane (1:19)gave3′,4′-dihydro-7′[2-(trimethylsilyl)-ethynyl]spiro[1,3-dioxolane-2,2′(1′H)-naphthalene](1.45 g). ¹H NMR (CDCl₃ 200 MHz) δ: 0.23 (s, 9H, SiMe₃), 1.93 (t, J=7Hz, 2CH₂), 2.95 (t, J=7 Hz, 2H, CH₂), 4.02 (s, 4H, OCH₂CH₂O), 7.03 (d,J=8 Hz, 1H, Ar), 7.17 (s, 1H, Ar), 7.21 (d, J=8 Hz, 1H, Ar).

C. 7′-Ethynyl-3′,4′-dihydrospiro[1,3-dioxolane-2,2′(1′H)-naphthalene]

A solution of3′,4′dihydro-7′[2-(trimethylsilyl)ethynyl]spiro[1,3-dioxolane-2,2′(1′H)-naphthalene](1.45 g, 5.02 mmol) and suspended K₂CO₃ (0.50 g) in methanol (20 ml) wasstirred at room temperature for 30 minutes. The solution was thenfiltered and concentrated in vacuo. The residue was absorbed onto silicagel (2 g) and purified by chromatography on silica gel (11 g) elutingwith diethyl ether:hexane (1:9) to give7′-ethynyl-3′,4′-dihydrospiro[1,3-dioxolane-2,2′(1′H)-naphthalene] as asolid (0.85 g). ¹H NMR (CDCl₃, 200 MHz) δ: 1.94 (t, J=7 Hz, 2H, CH₂),2.95 (s, 2H, CH₂), 2.98 (t, J=7 Hz, 2H, CH₂), 3.01 (s, 1H, ethynylH),4.02 (s, 4H, OCH₂CH₂O), 7.07 (d, J=8 Hz, 1H, Ar), 7.19 (s, 1H, Ar), 7.24(d, J=8 Hz, 1H, Ar).

D. 7-Ethynyl-2-tetralone

A solution of7′-ethynyl-3′,4′-dihydrospiro[1,3-dioxolane-2,2′(1′H)naphthalene] (0.85g, 3.9 mmol) in THF (15 ml) and 1N HCl (5 ml) was stirred overnight atroom temperature. Concentrated HCl (2×0.5 ml) was then added in twoaliquots 2 hours apart. After stirring a further 2 hours the solutionwas diluted with diethyl ether, the aqueous phase was separated, and thesolution dried (MgSO₄) and concentrated in vacuo. The residue waspurified by chromatography on silica gel (15 g) eluting with diethylether:hexane (1:9→1:4) to give 7-ethynyl-2-tetralone as a solid (0.31g). ¹H NMR (CDCl₃, 200 MHz) δ: 2.54 (t, J=7 Hz, 2H, CH₂), 3.05 (s, 1H,ethynylH), 3.06 (t, J=7 Hz, 2H, CH₂), 3.56 (s, 2H, CH₂), 7.18 (d, J=8Hz, 1H, Ar), 7.26 (s, 1H, Ar), 7.34 (d, J=8 Hz, 1H, Ar).

EXAMPLE 1 3-Amino-9-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one

A solution of sodium ethoxide was prepared by adding freshly cut sodium(2.72 g, 118 mmoles) to absolute ethanol (350 ml). Guanidinehydrochloride (11.3 g, 118 mmoles) was added and the mixture was stirredand heated to reflux under a nitrogen atmosphere. A solution of ethyl7-bromo-3,4-dihydro-2-hydroxy-1-naphthoate (11.72 g, 39.4 mmoles) inabsolute ethanol (75 ml) was added dropwise over 2.5 hours. Refluxingwas continued for an additional 21.5 hours, after which time the mixturewas cooled to room temperature and filtered. Ethanol was evaporatedunder reduced pressure to give a yellow-colored foam which was dissolvedin 0.1 N NaOH (100 ml). The basic solution was extracted with ether andneutralized with acetic acid: water (1:9) to cause precipitation of theproduct. The precipitate was collected, washed with water and ether, anddried to give 3-amino-9-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one asan off-white powdery solid. (6.45 g, 53%) ¹H NMR (DMSO-d₆, 80 MHz) δ:2.45-2.90 (m, 4H, CH₂CH₂); 6.80 (br s, 2H, NH₂); 7.03-7.29 (m, 2H, ArH);8.60-8.75 (m, 1H, Ar); 11.0 (br s, 1H, NH). Anal. Calculated forC₁₂H₁₀BrN₃O.H₂O C, 46.47; H, 3.90; Br, 25.76; N, 13.55. Found: C, 46.58;H, 3.85; N, 13.60; Br, 25.87.

The following compounds were prepared from appropriately substitutedmethyl or ethyl 3,4-dihydro-2-hydroxy-1-naphthoates, using the proceduredescribed in the above example without significant modification:

X ¹HNMR (200 MHz)^(a) in DMSO-d₆ ^(a), (δ) 6-CH₃ ^(b)1.26(d, J=6.8Hz,3H, CH₃); 2.62(dd, J=16.9, 6.4Hz, 1H, H⁵); 3.01(dd, J=16.5, 6.1Hz, H⁵);3.11(m, 1H, H⁶); 7.21-7.29(m, 3H, Ar); 8.25-8.28(m, 1H, Ar). 7-F2.48-2.63(m, 2H, CH₂); 2.70-2.84(m, 2H, CH₂); 6.72(br s, 2H, NH₂);6.88(ddd, J=8, 8, 2Hz, 1H, Ar); 7.14(ddd, J= 8, 8, 6Hz, 1H, Ar); 8.30(d,J=8Hz, 1H, Ar); 10.93(br s, 1H, NH). 7-Cl 2.56(m, 2H, CH₂); 2.88(m, 2H,CH2); 6.71(s, 2H, NH2); 7.14(d, J=4Hz, 2H, Ar); 8.45(t, J=4Hz, 1H, Ar);10.92(s, 1H, NH). 7-Br ^(c)2.5-3.0(m, 4H[partially obscured by DMSO],CH₂CH₂); 6.78(br s, 2H, NH₂); 6.99-7.40(m, 2H, Ar); 8.46-8.57(m, 1H,Ar); 11.1(br s, 1H, NH). 7-I 2.50-2.58(m, 2H, CH₂); 2.79-2.88(m, 2H,CH₂); 6.73(br s, 2H, NH₂); 6.89(t, J=8Hz, 1H, Ar); 7.55(dd, 8, 1Hz, 1H,Ar); 8.49(dd, J=8, 1Hz, 1H, Ar); 10.96(br s, 1H, NH). 7-CH₃ 2.22(s, 3H,CH₃); 2.46-2.55(m, 2H, CH₂); 2.65-2.73(m, 2H, CH₂); 6.60(s, 2H, NH_(?));6.90(m, 1H, Ar); 7.00(t, J= 7.6Hz, 1H, Ar); 8.29(d, J=7.5Hz, 1H, Ar);10.85(br s, 1H, NH). 7-phenyl 2.39-2.72(m, 4H, CH₂CH₂); 6.68(br s, 2H,NH₂); 7.00(dd, J=7.8, 1Hz, 1H, Ar); 7.20(t, J=7.8Hz, 1H, Ar);7.30-7.47(m, 5H, Ar); 8.45(d, J=7.7Hz, 1H, Ar). 8-F 2.53(m, 2H, CH₂);2.77(m, 2H, CH₂); 6.65(br s, 2H, NH₂); 6.87-7.01(m, 2H, Ar); 8.45(dd,J=8.5, 6.3Hz, 1H, Ar); 10.93(br s, 1H, NH). 8-Cl 2.54(m, 2H, CH₂);2.77(m, 2H, CH₂); 6.72(br s, 2H, NH₂); 7.17(d, J=8.2Hz, 1H, Ar); 7.19(s,1H, Ar); 8.45(d, J= 8.2Hz, 1H, Ar); 10.98(br s, 1H, NH). 8-Br 2.55(t,J=7.5Hz, 2H, CH₂); 2.79(t, J=7.4Hz, 2H, CH₂); 6.75(br s, 2H, NH₂);7.32(dd, J=8.4, 2.3Hz, 1H, Ar); 7.34(s, 1H, Ar); 8.40(d, J=8.4Hz, 1H,Ar); 11.00(br s, 1H, NH). 9-F 2.54-2.77(m, 4H, CH₂CH₂); 6.70-6.86(m, 3H,NH₂ + Ar); 7.10-7.16(m, 1H, Ar); 8.21-8.27(m, 1H, Ar). 9-I 2.47-2.75(m,4H[partially obscured by DMSO], CH₂CH₂); 6.74(br s, 2H, NH₂); 6.93(d,J=8.0Hz, 1H, Ar); 7.36(dd, J=8.0, 1.9Hz, 1H, Ar); 8.81(d, J=1.9Hz, 1H,Ar); 11.00(br s, 1H, NH). 9-CH₃ 2.23(s, 3H, CH₃); 2.47-2.56(m, 2H, CH₂);2.65-2.73(m, 2H, CH₂); 6.61(br s, 2H, NH₂); 6.82(dd, J=7.5, 1.2Hz, 1H,Ar); 6.99(d, J=7.4Hz, 1H, Ar); 8.23(d, J=1.2Hz, 1H, Ar); 10.85(br s, 1H,NH). 9-ethynyl 2.45-2.63(m, 2H, CH₂); 2.68-2.85(m, 2H, CH₂); 4.01(s, 1H,CH); 6.71(br s, 2H, NH₂); 7.13(s, 2H, Ar); 8.57(s, 1H, Ar); 10.99(br s,1H, NH). 9-phenyl 2.57-2.84(m, 4H, CH₂CH₂); 6.70(br s, 2H, NH₂); 7.23(d,J=7.8Hz, 1H, Ar); 7.31-7.36(m, 2H, Ar); 7.46(t, J=7.8Hz, 2H, Ar);7.59(d, J=7.1Hz, 2H, Ar); 8.79(d, J=2Hz, 1H, Ar); 10.95(br s, 1H, NH).9-OC₂H₅ 1.29(t, J=7Hz, 3H, CH₃); 2.43-2.60(m, 2H, ArCH₂); 2.60-2.75(m,2H, ArCH₂); 3.93(q, J=7Hz, 2H, OCH₂); 6.60(dd, J=8, 3Hz, 1H, Ar);6.64(br s, 2H, NH₂); 6.99(d, J=8Hz, 1H, Ar); 8.09(d, J=3Hz, 1H, Ar).9-SCH₃ 2.42(s, 3H, CH₃); 2.46-2.59(m, 2H, CH₂); 2.64-2.78(m, 2H, CH₂);6.68(br s, 2H, NH₂); 6.93(dd, J=8, 2Hz, 1H, Ar); 7.07(d, J=8Hz, 1H, Ar);8.43(d, J=2Hz, 1H, Ar); 10.91(br s, 1H, NH). 9-SC₂H₅ 1.21(t, J=7Hz, 3H,CH₃); 2.48-2.60(m, 2H, ArCH₂); 2.55-2.69(m, 2H, ArCH₂); 2.88(q, J=7Hz,2H, SCH₂); 6.65(br s, 2H, NH₂); 7.00(dd, J=8, 2Hz, 1H, Ar); 7.07(d,J=8Hz, 1H, Ar); 8.47(d, J=2Hz, 1H, Ar). 10-Cl^(c) 2.50-2.94(m,4H[partially obscured by DMSO], CH₂CH₂); 6.75(br s, 2H, NH₂); 7.16(m,2H, Ar); 8.47(m, 1H, Ar); 10.97(br s, 1H, NH). 6,6-(CH₃)₂ 1.18(s, 6H,(CH₃)₂); 2.45(s, 2H, CH₂); 6.63(br s, 2H, NH₂); 7.03-7.16(m, 2H, Ar);7.23-7.31(m, 1H, Ar); 8.47-8.54(m, 1H, Ar); 10.89(br s, 1H, NH).6-CH₃-8-Cl 1.12(d, J=7Hz, 3H, CH₃); 2.35(dd, J=16.2, 6.6Hz, 1H, C⁵H);2.72(dd, J=16.1, 5.9Hz, 1H, C⁵H); 2.95(m, 1H, C⁶H); 6.69(br s, 2H, NH₂);7.17(dd, J=9, 2Hz, 1H, Ar); 7.19(s, 1H, Ar); 8.49(d, J=9Hz, 1H, Ar);10.96(br s, 1H, NH). 6-CH₃-9-Cl 1.10(d, J=7Hz, 3H, CH₃); 2.35(dd, J=16,7Hz, 1H, C⁵H); 2.72(dd, J=16, 6Hz, 1H, C⁵H); 2.94(m, 1H, C⁶H); 6.75(brs, 2H, NH₂); 7.08(dd, J=8, 2Hz, 1H, Ar); 7.16(d, J=8Hz, 1H, Ar); 8.54(d,J=2Hz, 1H, Ar); 11.01(br s, 1H, NH). 7,8-benzo 2.65(m, 2H, CH₂); 3.19(m,2H, CH₂); 6.72(br s, 2H, NH₂); 7.37-7.48(m, 2H, Ar); 7.69(d, J=8.8Hz,1H, Ar); 7.81(d, J=8.0Hz, 1H, Ar); 8.06(d, J=8.4Hz, 1H, Ar); 8.68(d,J=8.8Hz, 1H, Ar); 10.96(br s, 1H, NH). 7,9-(CH₃)₂ ^(b)2.23(s, 3H, CH₃);2.25(s, 3H, CH₃); 2.77-2.91(m, 4H, CH₂CH₂); 6.99(s, 1H, Ar); 7.89(s, 1H,Ar). 8,9-Cl₂ 2.47-2.82(m, 4H[partially obscured by DMSO], CH₂CH₂);6.82(br s, 2H, NH₂); 7.40(s, 1H, Ar); 8.67(s, 1H, Ar); 11.09(br s, 1H,NH). 8,9-(OCH₃)₂ ^(d)2.53(m, 2H, CH₂); 2.71(m, 2H, CH₂); 3.71(s, 3H,CH₃); 3.74(s, 3H, CH₃); 6.58(br s, 2H, NH₂); 6.78(s, 1H, Ar); 8.21(s,1H, Ar); 10.82(br s, 1H, NH). All compounds gave elemental analysesconsistent with the indicated structures. ^(a)Except where indicated.^(b)TFA-d, 300 MHz ^(c)80 MHz ^(d)300 MHz

EXAMPLE 2 3-Amino-9-bromobenzo[f]quinazolin-1(2H)-one

A. N-(9-Bromo-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

3-Amino-9-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one (5.83 g, 20mmoles) and pivalic anhydride (200 ml) were stirred and heated to 185°C. under a nitrogen atmosphere for 1 hour. After cooling, excess pivalicanhydride was evaporated under reduced pressure. The residue wastriturated with ether:hexanes (1:1) (200 ml), filtered and dried to giveN-(9-bromo-1,2,5,6-tetrahydro-1-oxo-benzo[f]quinazolin-3-yl)pivalamideas an off-white solid. (6.1 g, 81%). ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.23(s, 9H, t-butyl); 2.73-2.85 (m, 4H, CH₂CH₂); 7.18 (d, J=8.1 Hz, 1H, Ar);7.34 (dd, J=7.8, 2.1 Hz, 1H, Ar); 8.70 (d, J=2.0 Hz, 1H, Ar); 11.35 (brs, 1H, NH).

B. N-(9-Bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

A mixture ofN-(9-bromo-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide(1.09 g, 2.9 mmoles) and pyridine (0.28 ml, 3.5 mmoles) in dry benzene(100 ml) was stirred and heated to reflux under a nitrogen atmosphere.N-Bromosuccinimide (0.57 g, 3.2 mmoles) was added in a single portion,and the mixture was vigorously stirred and refluxed for 1.5 hours. Aftercooling, benzene and excess pyridine were removed under reducedpressure, leaving a light yellow residue which was then triturated withmethanol:methylene chloride (1:1), filtered and dried to giveN-(9-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide. (0.4 g,37%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.26 (s, 9H, t-butyl); 7.58 (d, J=9.0Hz, 1H, Ar); 7.74 (dd, J=8.7, 2.1 Hz, 1H, Ar); 7.98 (d, J=8.8 Hz, 1H,Ar); 8.25 (d, J=9.0 Hz, 1H, Ar); 9.92 (d, J=2.0 Hz, 1H, Ar); 11.35 (brs, 1H, NH); 12.35 (br s, 1H, NH).

C. 3-Amino-9-bromobenzo[f]quinazolin-1(2H)-one

A solution ofN-(9-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.15 g,0.4 mmole) in 0.75 N NaOH (7 ml) was stirred and heated to 75° C. undera nitrogen atmosphere for 10.5 hours. The solution was cooled and madeslightly acidic with acetic acid to cause precipitation of the product.The precipitate was collected, washed successively with water, methanoland ether, and dried to give 3-amino-9-bromobenzo[f]quinazolin 1(2H)-oneas an off-white solid. (0.115 g, 99%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 6.64(br s, 2H, NH₂); 7.31 (d, J=8.8 Hz, 1H, Ar); 7.57 (dd, J=8.5, 1.9 Hz,1H, Ar); 7.83 (d, J=8.6 Hz, 1H, Ar); 8.02 (d, J=9.0 Hz, 1H, Ar); 9.83(s, 1H, Ar); 11.28 (br 5, 1H, NH).

The following compounds were prepared from appropriately substituted5,6-dihydrobenzo[f]quinazolin-1(2H)-ones, using the same route describedin the above example

X ¹H NMR (200 MHz) in DMSO-d6 (δ) 7-F 6.64(br s, 2H, NH₂); 7.24(ddd,J=11, 8, 1Hz, 1H, Ar); 7.37(d, J=9Hz, 1H, Ar); 7.57(ddd, J=8, 8, 6Hz,1H, Ar); 8.16(d, J=9Hz, 1H, Ar); 9.42(d, J=9Hz, 1H, Ar); 11.21(br s, 1H,NH). 7-Cl 6.64(br s, 2H, NH₂); 7.44(d, J=9.4Hz, 1H, Ar); 7.51-7.61(m,2H, Ar); 8.31(d, J=9.4Hz, 1H, Ar); 9.67(dd, J=6.9, 2.7Hz, 1H, Ar);11.22(br s, 2H, NH). 7-Br 6.65(s, 2H, NH₂); 7.44(d, J=9.2Hz, 1H, Ar);7.49(t, J= 7.6Hz, 1H, Ar); 7.77(dd, J=7.6, 1.1Hz, 1H, Ar); 8.29(d,J=9.3Hz, 1H, Ar); 9.73(dd, J=8.6, 0.8Hz, 1H, Ar); 11.25(br s, 1H, NH).7-I 6.65(br s, 2H, NH₂); 7.31(t, J=8.0Hz, 1H, Ar); 7.41(d, J=9.2Hz, 1H,Ar); 8.04(dd, J=7.4, 1.0Hz, 1H, Ar); 8.16(d, J=9.2Hz, 1H, Ar); 9.76(d,J=8.6Hz, 1H, Ar); 11.25(br s, 1H, NH). 8-F 6.54(br s, 2H, NH₂); 7.35(d,J=8.8Hz, 1H, Ar); 7.47(dt, J=9.1, 2.9Hz, 1H, Ar); 7.68(dd, J=10.0,2.9Hz, 1H, Ar); 8.01(d, J=8.8Hz, 1H, Ar); 9.68(dd, J=9.1, 6.1Hz, 1H,Ar); 11.18(br s, 1H, NH). 8-Cl 6.61(br s, 2H, NH₂); 7.34(d, J=8.8Hz, 1H,Ar); 7.59(dd, J=9.2, 2.2Hz, 1H, Ar); 7.98(d, J=2.2Hz, 1H, Ar); 8.00(d,J=8.8Hz, 1H, Ar); 9.62(d, J=9.2Hz, 1H, Ar); 11.23(br s, 1H, NH). 9-F6.63(br s, 2H, NH₂); 7.23-7.37(m, 2H, Ar); 7.91- 8.06(m, 2H, Ar);9.34(dd, J=13.3, 2.5Hz, 1H, Ar); 11.21 (br s, 1H, NH). 9-Cl 6.62(br s,2H, NH₂); 7.30(d, J=9.0Hz, 1H, Ar); 7.45(dd, J=8.5, 2.2Hz, 1H, Ar);7.90(d, J=8.6Hz, 1H, Ar); 8.04(d, J=8.9Hz, 1H, Ar); 9.68(d, J=1.8Hz, 1H,Ar); 11.25(br s, 1H, NH). 9-I 6.61(br s, 2H, NH₂); 7.30(d, J=8.9Hz, 1H,Ar); 7.63-7.75(m, 2H, Ar,); 8.00(d, J=8.9Hz, 1H, Ar); 10.05(s, 1H, Ar);11.25(br s, 1H, NH). 6-CH₃-8-Cl 2.62(s, 3H, CH₃); 6.57(br s, 2H, NH₂);7.23(s, 1H, Ar); 7.60(dd, J=9.2, 2.3Hz, 1H, Ar); 7.96(d, J=2.3Hz, 1H,Ar); 9.71(d, J=9.2Hz, 1H, Ar). 6-CH₃-9-Cl 2.62(s, 3H, CH₃); 6.62(br s,2H, NH₂); 7.19(s, 1H, Ar); 7.48(dd, J=8.8, 2.2Hz, 1H, Ar); 7.98(d,J=8.8Hz, 1H, Ar); 9.76(d, J=2.2Hz, 1H, Ar); 11.21(br s, 1H, NH). 8,9-Cl₂6.72(br s, 2H, NH₂); 7.35(d, J=9Hz, 1H, Ar); 8.02(d, J= 9Hz, 1H, Ar);8.20(s, 1H, Ar); 9.84(s, 1H, Ar); 11.38(br s, 1H, NH). 8-Br-9-OC₂H₅*1.44(t, J=6.9Hz, 3H, CH₃); 4.20(q, J=7.0Hz, 2H, CH₂); 6.63(s, 2H, NH₂);7.17(d, J=8.9Hz, 1H, Ar); 7.93(d, J=8.9Hz, 1H, Ar); 8.16(s, 1H, Ar);9.30(s, 1H, Ar); 11.19(br s, 1H, NH). 8-NO₂-9-Br 6.92(br s, 2H, NH₂);7.44(d, J=9Hz, 1H, Ar); 8.20(d, J= 9Hz, 1H, Ar); 8.72(s, 1H, Ar);10.05(s, 1H, Ar); 11.5(br s, 1H, NH). *Prepared by bromination in situof the corresponding 9-ethoxy-substituted intermediate during theNBS-aromatization step.

All compounds gave elemental analyses consistent with the indicatedstructures.

EXAMPLE 3 9-Bromo-5,6-dihydro-3-methylbenzo[f]quinazolin-1(2H)-one

A solution of sodium ethoxide was prepared by adding freshly cut sodium(0.73 g, 32 mmoles) to absolute ethanol (40 ml). Acetamidinehydrochloride (3.2 g, 34 mmoles) was added and the mixture was stirredand heated to reflux under a nitrogen atmosphere. A solution of methyl7-bromo-3,4-dihydro-2-hydroxy-1-naphthoate (2.98 g, 10.5 mmoles) in asmall volume of absolute ethanol was added rapidly.

After 20 hours of refluxing, the mixture was cooled and neutralized withglacial acetic acid to cause precipitation of the product. Theprecipitate was collected, washed with water and ethanol, and dried togive 9-bromo-5,6-dihydro-3-methylbenzo[f]quinazolin-1(2H)-one as a whitesolid. (2.21 g, 72%) ¹H NMR (DMSO-d₆, 200 MHz) δ 2.30 (s, 3H, CH₃);2.65-2.85 (m, 4H, CH₂CH₂); 7.17 (d, J=8.0 Hz, 1H, Ar); 7.35 (dd, J=8.0,2.2 Hz, 1H, Ar); 8.76 (d, J=2.2 Hz, 1H, Ar); 12.67 (br s, 1H, NH).

The following compounds were prepared from appropriately substitutedmethyl or ethyl 3,4-dihydro-2-hydroxy-1-naphthoates, using the proceduredescribed in the above example without significant modification:

X 1HNMR (200 MHz)^(a) in DMSO-d6 (δ) 7-Cl 2.30(s, 3H, CH₃); 2.71(t,J=8.2Hz, 2H, CH₂); 2.94(t, J= 8.2Hz, 2H, CH₂); 7.23(t, J=8Hz, 1H, Ar);7.31(dd, J= 8, 2Hz, 1H, Ar); 8.57(dd, J=8, 2Hz, 1H, Ar); 12.61(br s, 1H,NH). 7-Br 2.30(s, 3H, CH₃); 2.71(m, 2H, CH₂); 2.94(m, 2H, CH₂); 7.16(t,J=8Hz, 1H, Ar); 7.45(dd, J=8, 1Hz, 1H, Ar); 8.60(dd, J=8, 1Hz, 1H, Ar);12.62(br s, 1H, NH). 7-I 2.30(s, 3H, CH₃); 2.65-2.75(m, 2H, CH₂);2.85-2.95(m, 2H, CH₂); 6.98(t, J=8Hz, 1H, Ar); 7.70(dd, J=8, 1Hz, 1H,Ar); 8.61(dd, J=8, 1Hz, 1H, Ar); 12.58(s, 1H, NH). 8-F 2.28(s, 3H, CH₃);2.61-2.91(m, 4H, CH₂CH₂); 6.96-7.12(m, 2H, Ar), 8.60(dd, J=8.6, 6.2Hz,1H, Ar); 12.56(br s, 1H, NH). 8-Br ^(b)2.31(s, 3H, CH₃); 2.70(t, 2H,CH₂); 2.86(t, 2H, CH₂); 7.41(dd, J=8.5, 2Hz, 1H, Ar); 7.45(d, J=2Hz, 1H,Ar); 8.53(d, J=8.4Hz, 1H, Ar); 12.60(br s, 1H, NH). 9-F 2.30(s, 3H,CH₃); 2.63-2.85(m, 4H, CH₂CH₂); 6.98(ddd, J= 11, 8.5, 3Hz, 1H, Ar);7.22(dd, J=8.2, 6.3Hz, 1H, Ar); 8.37(dd, J=11.8, 3Hz, 1H, Ar). 9-Cl2.30(s, 3H, CH₃); 2.64-2.87(m, 4H, CH₂CH₂); 7.23(s, 2H, Ar); 8.63(s, 1H,Ar); 12.66(br s, 1H, NH). 9-I 2.30(s, 3H, CH₃); 2.62-2.85(m, 4H,CH₂CH₂); 7.02(d, J=8Hz, 1H, Ar); 7.51(dd, J=8, 2Hz, 1H, Ar); 8.93(d,J=2Hz, 1H, Ar); 12.62(br s, 1H, NH). 9-CH₃ ^(b)2.31(s, 3H, CH3); 2.30(s,3H, ArCH₃); 2.63-2.72(m, 2H, CH₂); 2.72-2.82(m, 2H, CH₂); 6.99(dd, J=8,1Hz, 1H, Ar); 7.10(d, J=8Hz, 1H, Ar); 8.41(d, J=1Hz, 1H, Ar); 12.55(brs, 1H, NH). ^(a)Except where indicated. ^(b)300 MHz

All compounds gave correct elemental analyses for the indicatedstructure.

EXAMPLE 4 9-Bromo-3-methylbenzo[f]quinazolin-1(2H)-one

A mixture of 9-Bromo-5,6-dihydro-3-methylbenzo[f]quinazolin-1(2H)-one(1.0 g, 3.4 mmoles), N-bromosuccinimide (0.63 g, 3.5 mmoles) andpyridine (0.3 ml, 3.7 mmoles) in dry benzene (350 ml) was reacted in thesame manner as for the corresponding 3-pivalamide (Example 2). Aftercooling, benzene and excess pyridine were removed under reducedpressure. The residue was triturated with methanol:water (1:1) andfiltered to leave a crude product which was recrystallized from methanolto give 9-bromo-3-methylbenzo[f]quinazolin-1(2H)-one as an off-whitesolid. (0.47 g, 37%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 2.57 (s, 3H, CH₃);7.73 (d, J=9.0 Hz, 1H, Ar); 7.86 (dd, J=8.6, 2.0 Hz, 1H, Ar); 8.09 (d,J=8.7 Hz, 1H, Ar); 8.41 (d, J=8.8 Hz, 1H, Ar); 9.92 (d, J=2.0 Hz, 1H,Ar).

The following compounds were prepared from appropriately substituted5,6-dihydro-3-methylbenzo[f]quinazolin-1(2H)-ones, using the sameprocedure described in the above example

X ¹H NMR (200 MHz)^(a) in DMSO-d₆ (δ) 7-Cl 2.43(s, 3H, CH₃); 7.70(t,J=7.7Hz, 1H, Ar); 7.78(d, J= 9.2Hz, 1H, Ar); 7.80(dd, J=7.7, 1.3Hz, 1H,Ar); 8.52(d, J=9.2Hz, 1H, Ar); 9.87(d, J=7.7Hz, 1H, Ar); 12.67(br s, 1H,NH). 7-Br ^(b)2.49(s, 3H, CH₃); 7.67(t, J=8.1Hz, 1H, Ar); 7.82(d,J=9.2Hz, 1H, Ar); 8.02(dd, J=7.6, 1.0Hz, 1H, Ar); 8.54(d, J=9.1Hz, 1H,Ar); 9.93(d, J=8.6Hz, 1H, Ar). 7-I 2.43(s, 3H, CH₃); 7.41(t, J=8.1Hz,1H, Ar); 7.73(d, J= 9.2Hz, 1H, Ar); 8.23(dd, J=7.4, 1.1Hz, 1H, Ar);8.35(d, J=9.2Hz, 1H, Ar); 9.94(d, J=8.6Hz, 1H, Ar); 12.64(br s, 1H, NH).8-F 2.41(s, 3H, CH₃); 7.54-7.72(m, 2H, ArH⁹); 7.85(dd, J= 9.8, 2.8Hz,1H, Ar); 8.22(d, J=9.0Hz, 1H, Ar); 9.88(dd, J=8.5, 6.0Hz, 1H, Ar);12.60(br s, 1H, NH). 8-Br ^(b)2.43(s, 3H, CH₃); 7.68(d, J=8.9Hz, 1H,Ar); 7.86(dd, J=9.2, 2.3Hz, 1H, Ar); 8.24(d, J=9.0Hz, 1H, Ar); 8.33(d,J=2.2Hz, 1H, Ar); 9.76(d, J=9.1Hz, 1H, Ar); 12.66(br s, 1H, NH). 9-F2.47(s, 3H, CH₃); 7.63(dt, J=8.6, 2.8Hz, 1H, Ar); 7.68(d, J=9.0Hz, 1H,Ar); 8.22(dd, J=9.0, 6.2Hz, 1H, Ar); 8.42(d, J=9.0Hz, 1H, Ar); 9.42(dd,J=8.8, 2.8Hz, 1H, Ar). 9-Cl 2.53(s, 3H, CH₃); 7.69(d, J=8.9Hz, 1H, Ar);7.72(dd, J= 8.6, 2.3Hz, 1H, Ar); 8.14(d, J=8.9Hz, 1H, Ar); 8.37(d,J=8.6Hz, 1H, Ar); 9.78(d, J=2.3Hz, 1H, Ar). 9-I 2.42(s, 3H, CH₃);7.63(d, J=8.7Hz, 1H, Ar); 7.81(d, J= 8.7Hz, 1H, Ar); 7.92(dd, J=8.7,1.6Hz, 1H, Ar); 8.22(d, J=8.7Hz, 1H, Ar); 10.24(d, J=8.7Hz, 1H, Ar);12.64(br s, 1H, NH). ^(a)Except where indicated. ^(b)300 MHz.

All compounds gave elemental analyses consistent with the indicatedstructures.

EXAMPLE 5 3-Amino-7,9-dimethylbenzo[f]quinazolin-1(2H)-one

A mixture of 3-amino-5,6-dihydro-7,9-dimethylbenzo[f]quinazolin-1(2H)one(0.25 g, 1.04 mmole) and 10% palladium on carbon (0.5 g) in diglyme (25ml) was vigorously stirred and refluxed under a nitrogen atmosphere for2.5 hours, and then filtered while still hot through a bed of celite.Diglyme was removed from the filtrate under reduced pressure, and theresidue was triturated with hot methanol, filtered, washed with methanoland ether, and dried to give3-amino-7,9-di-methylbenzo[f]quinazolin-1(2H)-one as an off-white solid.(0.14 g, 55%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 2.43 (s, 3H, CH₃); 2.60 (s,3H, CH₃); 6.48 (s, 2H, NH₂); 7.14 (s, 1H, Ar); 7.25 (d, J=9.2 Hz, 1H,Ar); 8.11 (d, J=9.1 Hz, 1H, Ar); 9.38 (s, 1H, Ar); 11.07 (s, 1H, NH).

The following compounds were prepared from the corresponding 5,6-dihydrocompounds in the same manner as described in the above example:

R X ¹H NMR (200 MHz)^(a) in DMSO-d₆ (δ) NH₂ 6-CH₃ 2.63(s, 3H, CH₃);6.52(s, 2H, NH₂); 7.18(s, 1H, Ar); 7.46(dt, J=8.1, 1.4Hz, 1H, Ar);7.59(dt, J=8.3, 1.4Hz, 1H, Ar); 7.97(dd, J=8.0, 1.2Hz, 1H, Ar); 9.69(d,J= 8.2Hz, 1H, Ar); 11.06(s, 1H, NH). NH₂ 7-CH₃ 2.64(s, 3H, CH₃); 6.50(brs, 2H, NH₂); 7.26-7.49(m, 3H, Ar); 8.17(d, J=8.5Hz, 1H, Ar); 9.55(d,J=8.5Hz, 1H, Ar); 11.09(br s, 1H, NH). NH₂ 9-CH₃ ^(b)2.47(s, 3H, CH3);6.48(br s, 2H, NH₂); 7.16-7.29(m, 2H, Ar); 7.75(d, J=8.2Hz, 1H, Ar);7.95(d, J=8.2Hz, 1H, Ar); 9.44(s, 1H, Ar); 11.09(br s, 1H, NH). CH₃9-CH₃ ^(c)2.42(s, 3H, pyr-CH₃); 2.56(s, 3H, ArCH₃); 7.48(dd, J= 8, 2Hz,1H, Ar); 7.55(d, J=9Hz, 1H Ar); 7.93(d, J=8Hz, 1H, Ar); 8.19(d, J=9Hz,1H, Ar); 9.65(d, J=1Hz, 1H, Ar); 12.52(br s, 1H, NH). ^(a)Except whereindicated. ^(b)The N-(5,6-dihydro)pivalamide derivative wasdehydrogenated, followed by removal of the pivaloyl group as describedin example 2. ^(c)300 MHz

The compounds gave elemental analyses consistent with the indicatedstructure.

EXAMPLE 6 3-Amino-9-methoxybenzo[f]quinazolin-1(2H)-one

A mixture ofN-(1,2,5,6-tetrahydro-9-methoxy-1-oxobenzo[f]quinazolin-3-yl)pivalamide(0.93 g, 2.84 mmoles) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.8g, 3.5 mmoles) in dry benzene (60 ml) was refluxed under a nitrogenatmosphere for 3 hours. After cooling, benzene was removed under reducedpressure and the residue was purified on a silica gel column elutingwith chloroform to giveN-(1,2-dihydro-9-methoxy-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.9g).

The N-pivaloyl protecting group was removed with aqueous NaOH in thesame manner as in example 2 to give3-amino-9-methoxybenzo[f]quinazolin-1(2H)-one as a white solid. (0.58 g,85%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 3.86 (s, 3H, CH₃); 6.51 (s, 2H, NH₂);7.08 (dd, J=8.8, 2.5 Hz, 1H, Ar); 7.12 (d, J=8.9 Hz, 1H, Ar); 7.77 (d,J=8.8 Hz, 1H, Ar); 7.93 (d, J=8.8 Hz, 1H, Ar); 9.18 (d, J=2.5 Hz, 1H,Ar); 11.03 (s, 1H, NH).

The following compounds were prepared from the correspondingN-(5,6-dihydro)pivalamides using the procedure described in the aboveexample

X 1H NMR (200 MHz) in DMSO-d6 (δ) 9-OC₂H₅ 1.39(t, J=6.9Hz, 3H, CH₃);4.26(q, J=7.0Hz, 2H, CH₂); 6.51(br s, 2H, NH₂); 7.06(dd, J=8.8, 2Hz, 1H,Ar); 7.11(d, J=8.8Hz, 1H, Ar); 7.76(d, J=8.8Hz, 1H, Ar); 7.92(d,J=8.8Hz, 1H, Ar); 9.18(d, J=2Hz, 1H, Ar); 11.03(br s, 1H, NH). 9-SCH₃2.55(s, 3H, SCH₃); 6.50(br s, 2H, NH₂); 7.19(d, J=9Hz, 1H, Ar); 7.32(dd,J=8.5, 2Hz, 1H, Ar); 7.78(d, J=8.5Hz, 1H, Ar); 7.95(d, J=9Hz, 1H, Ar);9.51(d, J=2Hz, 1H, Ar); 11.04(br s, 1H, NH). 9-SC₂H₅ 1.31(t, J=7Hz, 3H,CH₃); 3.07(q, J=7Hz, 2H, CH₂); 6.64(br s, 2H, NH₂); 7.21(d, J=9Hz, 1H,Ar); 7.35(dd, J= 8.4, 2Hz, 1H, Ar); 7.79(d, J=8.4Hz, 1H, Ar); 7.95(d,J=9Hz, 1H, Ar); 9.59(s, 1H, Ar); 11.05(br s, 1H, NH).

All compounds gave elemental analyses consistent with the indicatedstructure.

EXAMPLE 7 3-Amino-9-hydroxybenzo[f]quinazolin-1(2H)-one

A solution of 3-amino-9-methoxybenzo[f]quinazolin-1(2H)-one (0.33 g,1.37 mmoles) in 48% HBr (8 ml) was stirred and heated at 110° C. for 50hours. After cooling, the mixture was neutralized by careful addition ofsolid NaOH to cause precipitation of the product. The precipitate wascollected, washed with water and dried.

The crude product was converted to the N-pivalamide derivative byreaction with pivalic anhydride in the same manner as in example 2, andpurified on a silica gel column eluting with 0 to 0.8%methanol:chloroform.

The pivaloyl group was removed with base in the same manner as inexample 2 to give 3-amino-9-hydroxybenzo[f]quinazolin-1(2H)-one as a tansolid. (0.22 g, 65%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 6.45 (br s, 2H, NH₂);6.93 (dd, J=8.6, 2.2 Hz, 1H, Ar); 7.03 (d, J=8.8 Hz, 1H, Ar); 7.67 (d,J=8.6 Hz, 1H, Ar); 7.86 (d, J=8.8 Hz, 1H, Ar); 9.01 (d, J=2.2 Hz, 1H,Ar); 9.77 (s, 1H, OH); 11.02 (br s, 1H, NH).

In a similar manner,3-amino-9-hydroxy-5,6-dihydrobenzo[f]quinazolin-1(2H)-one was preparedfrom 3-amino-9-methoxy-5,6-dihydrobenzo-[f]quinazolin-1(2H)-one. (53%)¹H NMR (DMSO-d₆, 200 MHz) δ: 2.40-2.70 (m, 4H, CH₂CH₂); 6.41 (dd, J=8.2,2.5 Hz, 1H, Ar); 6.59 (br s, 2H, H₂); 6.88 (d, J=8.2 Hz, 1H, Ar); 7.96(d, J=2.5 Hz, 1H, Ar); 8.91 (s, 1H, ArOH); 10.87 (br s, 1H, NH). Anal.Calculated for C₁₂H₁₁N₃O₂.3/10H₂O.5/4CH₃OH: C, 57.94; H, 6.09; N, 15.30.Found: C, 57.97; H, 5.95; N, 15.34.

EXAMPLE 8 3-Amino-6-(methoxymethyl)benzo[f]quinazolin-1(2H)-one

A.N-(6-(Bromomethyl)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl))pivalamide

To a solution ofN-(6-methyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (1.76 g,5.7 mmoles) in dry benzene (150 ml) was added N-bromosuccinimide (1.01g, 5.7 mmoles) and dibenzoyl peroxide (15 mg). The mixture was heated toreflux under a nitrogen atmosphere for 2.5 hours. After cooling, benzenewas removed under reduced pressure, and the residue was purified on asilica gel column eluting with chloroform to giveN-(6-(bromomethyl)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamideas an off-white solid. (1.4 g, 57%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.27(s, 9H, t-butyl); 5.26 (s, 2H, CH₂Br); 7.63-7.81 (m, 3H, Ar); 8.26 (dd,J=7.6, 2.0 Hz, 1H, Ar); 9.81 (dd, J=7.8, 2.0 Hz, 1H, Ar); 11.27 (s, 1H,NH); 12.33 (s, 1H, NH). Anal. Calculated for C₁₈H₁₈BrN₃O₂: C, 55.68; H,4.67; N, 10.82. Found C, 55.48; H, 4.84; N, 10.57.

B. 3-Amino-6-(methoxymethyl)benzo[f]quinazolin-1(2H)-one

A solution ofN-(6-(bromomethyl)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide(0.28 g, 0.72 mmole) in 0.3 M sodium methoxide (25 ml) was stirred andheated at 650° C. under a nitrogen atmosphere for 4 hours. Aftercooling, the mixture was acidified to pH 6 with glacial acetic acid, andthen all solvent was removed under reduced pressure. The residue wastriturated with water (20 ml), then filtered, washed with water andacetone, and dried to give3-amino-6-(methoxymethyl)benzo[f]quinazolin-1(2H)-one as an off-whitesolid. (0.12 g, 58%) ¹H NMR (DMSO-d₆, 200 MHz) d 3.39 (s, 3H, OCH₃);4.85 (s, 2H, CH₂); 6.54 (br s, 2H, NH₂); 7.33 (s, 1H, Ar); 7.44 (dt,J=6.9, 1.4 Hz, 1H, Ar); 7.59 (dt, J=6.9, 1.4 Hz, 1H, Ar); 7.96 (dd,J=8.2, 1.0 Hz, 1H, Ar); 9.69 (d, J=8 Hz, 1H, Ar); 11.11 (br s, 1H, NH);11.91 (br s, <1H, pyr-NH⁺). Anal. Calculated forC₁₄H₁₃N₃O₂.1/2HOAc.1/10H₂O: C, 62.75; H, 5.34; N, 14.64. Found C, 62.74;H, 5.31; N, 14.64.

In a similar manner,3-amino-6-(hydroxymethyl)benzo[f]quinazolin-1(2H)-one was prepared bysubstituting 0.6 N aqueous NaOH in place of sodium methoxide. (32%) ¹HNMR (DMSO-d₆, 200 MHz) δ: 4.95 (d, J=4.2 Hz, 2H, CH₂); 5.44 (t, J=4.2Hz, 1H, OH); 6.52 (br s, 2H, NH₂); 7.40 (s, 1H, Ar); 7.43 (dt, J=7.9,1.5 Hz, 1H, Ar); 7.57 (dt, J=7.9, 1.5 Hz, 1H, Ar); 7.94 (dd, J=7.9, 1.5Hz, 1H, Ar); 9.70 (d, J=7.9 Hz, 1H, Ar); 11.10 (br s, 1H, NH). Anal.Calculated for C₁₃H₁₁N₃O₂.CH₃COOH: C, 59.80; H, 5.02; N, 13.95. Found:C, 59.80; H, 5.04; N, 13.91.

EXAMPLE 9 3-Amino-9-bromo-10-nitrobenzo[f]quinazolin-1(2H)-one

To a stirred solution of 3-amino-9-bromobenzo[f]quinazolin-1(2H)-one(3.0 g, 10.3 mmoles) in 98% sulphuric acid (125 ml) at 0-50° C. wasadded finely divided potassium nitrate (1.05 g, 10.3 mmoles) in severalportions over a 20 minute period. After stirring at 0° C. for 2 hoursmore, the mixture was poured onto 1000 ml of crushed ice and allowed tostand until all the ice melted. A fine, light yellow precipitate wasthen filtered, washed with water, and resuspended in 2 N NaOH withstirring for 3 hours. After this time, the suspension was filtered, andthe solid was resuspended in dilute aqueous acetic acid with vigorousstirring and sonication. The bright yellow solid was filtered, washedwith water, dried and triturated with boiling ethanol (500 ml) to give,after drying, 3-amino-9-bromo-10-nitrobenzo[f]quinazolin-1(2H)-one.(2.74 g, 72%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 6.91 (br s, 2H, NH₂); 7.42(d, J=9 Hz, 1H, Ar); 7.86 (d, J=7 Hz, 1H, Ar); 8.06 (d, J=9 Hz, 1H, Ar);8.13 (d, J=7 Hz, 1H, Ar); 11.25 (br s, 1H, NH).

The following compounds were prepared from the correspondingbenzo[f]quinazolin-1(2H)-ones in the same manner as described in theabove example:

X 1H NMR (200 MHz)^(a) in DMSO-d6 (δ) 7-NO₂ ^(b) 7.16(br s, 2H, NH₂);7.51(d, J=9.5Hz, 1H, Ar); 7.72(t, J=7.8Hz, 1H, Ar); 8.03(dd, J=7.8,1.2Hz, 1H, Ar); 8.23(d, J=9.5Hz, 1H, Ar); 10.18(d, J=7.3Hz, 1H, Ar).8-NO₂ ^(b) 6.85(br s, 2H, NH₂); 7.43(d, J=8.9Hz, 1H, Ar); 8.30(d,J=8.9Hz, 1H, Ar); 8.32(dd, J=9.4, 2.6Hz, Ar); 8.88(d, J=2.6Hz, 1H, Ar);9.76(d, J=9.4Hz, 1H, Ar); 11.38(br s, 1H, NH). 5,6-dihydro-^(d)2.75-2.99(br m, 4H, CH₂CH₂); 8.02-8.05(d, J=3Hz, 1H, 8-NO₂ ^(c) Ar);8.05-8.08(m, 1H, Ar); 8.40(br s, 3H, NH3⁺); 8.55-8.61(d, J=5Hz, 1H, Ar).10-NO₂ ^(b) 6.82(s, 2H, NH₂); 7.40(d, J=9Hz, 1H, Ar); 7.54(t, J= 7.8Hz,1H, Ar); 8.04(d, J=7.8Hz, 1H, Ar); 8.13(d, J= 9Hz, 1H, Ar); 8.17(d,J=7.8Hz, 1H, Ar); 11.20(br s, 1H, NH). 7-NO₂-8-F 6.77(br s, 2H, NH₂);7.56(d, J=9.3Hz, 1H, Ar); 7.82(t, J=9.8Hz, 1H, Ar); 7.92(d, J=9.3Hz, 1H,Ar); 9.98(dd, J=9.7, 5.6Hz, 1H, Ar); 11.42(br s, 1H, NH). 7-NO₂-8-Br6.93(br s, 2H, NH₂); 7.52(d, J=9.4Hz, 1H, Ar); 7.73(d, J=9.3Hz, 1H, Ar);7.99(d, J=9.4Hz, 1H, Ar); 9.76(d, J=9.3Hz, 1H, Ar); 11.6(br s, 1H, NH).9-Br-5,6- 2.61(t, J=8Hz, 2H, CH₂); 2.86(t, J=8Hz, 2H, CH₂); dihydro-8-7.06(br s, 2H, NH₂); 7.89(s, 1H, Ar); 8.93(s, 1H, Ar); NO₂ 11.23(br s,1H, NH). 8,10-(NO₂)₂ ^(e) 7.15(br s, 2H, NH₂); 7.54(d, J=9.0Hz, 1H, Ar);8.41(d, J=9.2Hz, 1H, Ar); 8.65(d, J=2.4Hz, 1H, Ar); 9.18(d, J=2.3Hz, 1H,Ar); 11.47(br s, 1H, NH). 8-F-10-NO₂ ^(f) 6.85(br s, 2H, NH₂); 7.44(d,J=8.9Hz, 1H, Ar); 8.05-8.20(m, 3H, Ar); 11.26(s, 1H, NH). ^(a)Exceptwhere noted. ^(b)Separated from a mixture of 7-, 8-, and 10-isomers byfractional crystallizations (diethyl ether: pivalic anhydride (2:1)and/or ethyl acetate: diethyl ether (1:1)) of the N-pivalamidederivatives, followed by removal of the pivaloyl group as described inexample 2. ^(c)Recrystallized from 9M H₂SO₄. ^(d)80 MHz ^(e)Two moles ofpotassium nitrate per mole of starting material was used. ^(f)Isolatedfrom the NaOH filtrate by neutralization, filtration of the resultingsolid, conversion of the water-washed and dried material to theN-pivalamide derivative as described in example 2, purification bysilica gel chromatography using chloroform as eluent, and removal of thepivaloyl group as described in example 2.

In a similar manner,5,6-dihydro-3-methyl-8-nitrobenzo[f]quinazolin-1(2H)-one was preparedfrom 5,6-dihydro-3-methylbenzo[f]quinazolin-1(2H)-one with the followingmodification. A solution of the reaction mixture in water wasneutralized (pH 7) with NaOH pellets to cause precipitation of the crudeproduct which was filtered, redissolved in 1 N NaOH, precipitated withacetic acid, filtered, washed with water and dried. The solid was thentriturated with hot methanol, filtered and dried to give the pureproduct. ¹H NMR (DMSO-d₆, 200 MHz) δ: 2.32 (s, 3H, CH₃); 2.76 (t, J=8.0Hz, 2H, CH₂); 2.99 (t, J=8.0 Hz, 2H, CH₂); 8.05-8.15 (m, 2H, Ar); 8.82(d, J=9.4 Hz, 1H, Ar); 12.8 (br s, 1H, NH).

All compounds gave elemental analyses consistent with the assignedstructures.

EXAMPLE 10 3-Amino-8-bromo-9-nitrobenzo[f]quinazolin-1(2H)-one

1,3-Diamino-5,6-dihydrobenzo[f]quinazoline (1.0 g, 4.7 mmol) wassuspended in glacial acetic acid (1 ml), and bromine (1.0 ml) was addeddropwise with stirring. The first few drops were rapidly decolorized,but on completion of the addition the solid had completely dissolved andthe solution remained a deep red. Stirring was continued at roomtemperature for a further two hours, the reaction mixture poured intowater (50 ml), and the yellow solid removed by filtration. The crudebromo-compound was dried overnight in vacuo at room temperature,suspended in M—HCl, and the suspension heated briefly to boiling. Thecooled suspension was filtered, the solid washed with water and dried invacuo overnight to yield the title compound (1.10 g, 66%) as a creamsolid, mp.>250° C. ¹H NMR (DMSO-d₆, 80 MHz) δ: 2.65-2.90 (m, 4H, ArCH₂),7.33-7.68 (m, 3H, Ar), 7.15-7.85 (br s, 2H, NH₂), 7.90-8.35 (br s, 2H,NH₂), 12.30-13.70 (br s, 1H, NH). Mass spectrum (EI): 290 (M⁺, 100%);211 ((M−79)⁺, 12.7%). Anal. Calculated for C₁₂H₁₁BrN₄.HCl.7/5H₂O: C,40.85; H, 4.23; N, 15.88. Found: C, 40.82; H, 3.52; N, 15.88.

To a mixture of fuming nitric acid (7 ml) and sulphuric acid (6 ml) at0° C. was added 1,3-diamino-8-bromo-5,6-dihydrobenzo[f]quinazoline (1.0g, 3.4 mmoles) in a single portion. The reaction mixture was stirred at0-5° C. for 45 minutes, and then slowly poured onto ice (15 g). Theresulting precipitate was filtered, washed with water (10 ml) and ether(10 ml), and resuspended in boiling 1N HCl (100 ml) for 1 hour. Aftercooling, the solid was filtered, triturated with hot ethanol, filteredagain, washed with ethanol and ether, and dried to give3-amino-8-bromo-9-nitrobenzo[f]quinazolin-1(2H)-one as a pale yellowsolid. (0.59 g, 45%) ¹H NMR (DMSO-d₆, 80 MHz) δ: 7.62-7.71 (d, J=7 Hz,1H, Ar); 7.77 (s, 3H, NH₃ ⁺); 8.23-8.34 (d, J=9 Hz, 1H, Ar); 8.59 (s,1H, Ar); 10.08 (s, 1H, Ar). Anal. Calculated for C₁₂H₇BrN₄O₃.1/2HNO₃.H₂OC, 37.47; H, 2.49; N, 16.39. Found C, 37.20; H, 2.24; N, 16.00.

EXAMPLE 11 3,10-Diamino-9-bromobenzo[f]quinazolin-1(2H)-one

A.N-(9-Bromo-1,2-dihydro-10-nitro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

Pivalic anhydride (20 ml) was reacted with3-amino-9-bromo-10-nitro-benzo[f]quinazolin-1(2H)-one (2.44 g, 7.28mmoles) in the same manner as in example 2. The product was purified bytrituration with hot ethyl acetate to giveN-(9-bromo-1,2-dihydro-10-nitro-1-oxobenzo[f]quinazolin-3-yl)pivalamideas a light yellow solid. (1.67 g, 55%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.25(s, 9H, t-butyl); 7.69 (d, J=8.8 Hz, 1H, Ar); 8.02 (d, J=8.7 Hz, 1H,Ar); 8.20 (d, J=8.8 Hz, 1H, Ar); 8.34 (d, J=9.0 Hz, 1H, Ar); 11.45 (brs, 1H, NH); 12.18 (br s, 1H, NH).

B.N-(10-Amino-9-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

A mixture ofN-(9-bromo-1,2-dihydro-10-nitro-1-oxobenzo[f]quinazolin-3-yl)pivalamide(0.8 g, 1.9 mmoles) and iron powder (0.44 g, 7.8 mmoles) inethanol:glacial acetic acid/1:1 (25 ml) was stirred and heated to refluxunder a nitrogen atmosphere for 3 hours. The reaction mixture was pouredinto chloroform:water/2:1 (150 ml) and neutralized by addition of solidsodium bicarbonate. The chloroform layer was separated, and the aqueousphase was washed twice with chloroform (50 ml each). Combined chloroformlayers were dried over sodium sulfate, filtered and evaporated underreduced pressure. The crude product was purified on a silica gel columneluting with chloroform to giveN-(10-amino-9-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamideas a bright yellow solid. (0.66 g, 89%) ¹H NMR (DMSO-d₆, 200 MHz) δ:1.27 (s, 9H, t-butyl); 6.51 (s, 2H, NH₂); 7.22 (d, J=8.4 Hz, 1H, Ar);7.51 (br d, J=9 Hz, 1H, Ar); 7.72 (d, J=8.4 Hz, 1H, Ar); 8.12 (d, J=9.0Hz, 1H, Ar); 11.40 (br s, 1H, NH); 12.45 (br s, 1H, NH).

C. 3,10-Diamino-9-bromobenzo[f]quinazolin-1(2H)-one

N-(10-Amino-9-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide(0.58 g, 1.5 mmoles) was reacted with aqueous sodium hydroxide asdescribed for the analogous 9-bromo compound (example 2). The productwas precipitated from the reaction mixture with acetic acid, filteredand washed with water to give3,10-diamino-9-bromobenzo[f]quinazolin-1(2H)-one as a yellow solid.(0.36 g, 80%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 6.49 (br s, 2H, NH₂); 6.69(br s, 2H, NH₂); 7.09 (d, J=8.4 Hz, 1H, Ar); 7.22 (d, J=8.9 Hz, 1H, Ar);7.56 (d, J=8.4 Hz, 1H, Ar); 7.90 (d, J=8.9 Hz, 1H, Ar); 11.47 (br s, 1H,NH).

The following compounds were prepared from the corresponding bromo-nitrocompounds as described in the above example:

X ¹H NMR (200 MHz) in DMSO-d₆ (δ) 7-NH₂-8-Br 7.42(d, J=9.2Hz, 1H, Ar);7.68(d, J=9.2Hz, 1H, Ar); 8.19(br s, 2H, NH₂); 8.62(d, J=9.2Hz, 1H, Ar);8.73(d, J=9.2Hz, 1H, Ar). 8-NH₂-9-Br 7.21(s, 1H, Ar); 7.40(d, J=8.9Hz,1H, Ar); 7.95(br s, 2H, NH₂); 8.01(d, J=9.4Hz, 1H, Ar); 9.63(s, 1H, Ar).8-NH₂-9-Br- 2.42-2.68(m, 4H, CH₂CH₂); 5.11(s, 2H, NH₂); 6.50(s, 2H,5,6-dihydro NH₂); 6.57(s, 1H, Ar); 8.46(s, 1H, Ar); 10.91(br s, 1H, NH).

All compounds gave elemental analyses consistent with the indicatedstructures.

EXAMPLE 12 3,9-Diaminobenzo[f]quinazolin-1(2H)-one

A. 3-Amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one

Ethyl 6-bromo-3,4-dihydro-2-hydroxy-1-naphthoate (6.0 g, 20.2 mmoles)was reacted with guanidine (6.9 g of hydrochloride salt, 72.2 mmoles) inthe same manner as in example 1. The product was precipitated fromaqueous sodium hydroxide with acetic acid, filtered, washed with waterand dried to give3-amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one as an off-whitesolid. (2.75 g, 46%) ¹H NMR (DMSO-d₆, 300 MHz) δ: 2.55 (t, J=7.5 Hz, 2H,CH₂); 2.79 (t, J=7.4 Hz, 2H, CH₂); 6.75 (br s, 2H, NH₂); 7.32 (dd,J=8.4, 2.3 Hz, 1H, Ar); 7.34 (s, 1H, Ar); 8.40 (d, J=8.4 Hz, 1H, Ar);11.00 (br s, 1H, NH).

B.N-(8-Bromo-1,2,5,6-tetrahydro-9-nitro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

To a stirred solution of3-amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one (2.56 g, 8.76mmoles) in 98% sulphuric acid (180 ml) at 0° C. was added a solution ofpotassium nitrate (0.89 g, 8.80 mmoles) in sulphuric acid (20 ml)dropwise over a 40 minute period. The reaction mixture was poured onto1000 ml of crushed ice and allowed to stand until all the ice melted. Alight yellow precipitate was filtered, washed with water, andresuspended in 1 N NaOH with stirring at 50° C. for 2 hours. After thistime, the suspension was neutralized with glacial acetic acid,refiltered and dried to obtain a light yellow solid.

The crude product was reacted with pivalic anhydride in the same manneras in example 2, and purified by two crystallizations from chloroform togiveN-(8-bromo-1,2,5,6-tetrahydro-9-nitro-1-oxo-benzo[f]quinazolin-3-yl)pivalamideas a light yellow solid. (0.68 g, 17%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.23(s, 9H, t-butyl); 2.78 (m, 2H, CH₂); 2.99 (m, 2H, CH₂); 7.80 (s, 1H,Ar); 8.30 (s, <1H, CHCl₃); 9.11 (s, 1H, Ar); 11.45 (br s, 1H, NH); 12.20(br s, 1H, NH).

C.N-(8-Bromo-1,2-dihydro-9-nitro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

N-(8-Bromo-1,2,5,6-tetrahydro-9-nitro-1-oxobenzo[f]quinazolin-3-yl)pivalamide(0.23 g, 0.5 mmole) was reacted with N-bromosuccinimide (0.12 g, 0.7mmole) and pyridine (0.06 ml, 0.8 mmole) in dry benzene (150 ml) in thesame manner as in example 2. The crude product was purified bytrituration with methanol:water (1:9), followed by filtration andwashing (water and methanol) to give, after drying,N-(8-bromo-1,2-dihydro-9-nitro-1-oxobenzo[f]quinazolin-3-yl)pivalamideas a pale yellow solid. (0.20 g, 94%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.27(s, 9H, t-Butyl); 7.76 (d, J=9.0 Hz, 1H, Ar); 8.32 (d, J=9.0 Hz, 1H,Ar); 8.65 (s, 1H, Ar); 10.21 (s, 1H, Ar); 11.40 (s, 1H, NH); 12.45 (brs, 1H, NH).

D. N-(9-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

N-(8-Bromo-1,2-dihydro-9-nitro-1-oxobenzo[f]quinazolin-3-yl)pivalamide(0.18 g, 0.43 mmole) was dissolved into ethanol (200 ml) with heating ina 500 ml Parr hydrogenation flask. A slurry of 10% palladium on carbon(0.13 g) in a small volume of ethanol was added, and the reaction wasbegun with 42.5 psi hydrogen pressure. When uptake of hydrogen hadceased (3.5 hours.), the reaction mixture was filtered through celite,and the solvent was removed under reduced pressure to leave a yellowsolid. The product was purified on a silica gel column eluting withmethanol:chloroform (1:99) to giveN-9-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide as a tansolid. (0.09 g, 63%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.25 (s, 9H, t-butyl);5.75 (br s, 2H, NH₂); 6.92 (dd, J=8.7, 2.2 Hz, 1H, Ar); 7.10 (d, J=8.5Hz, 1H, Ar); 7.64 (d, J=8.6 Hz, 1H, Ar); 7.91 (d, J=8.8 Hz, 1H, Ar);8.77 (d, J=1.4 Hz, 1H, Ar); 11.10 (br s, 1H, NH);. 12.10 (br s, 1H, NH).

E. 3,9-Diaminobenzo[f]quinazolin-1(2H)-one

N-(9-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.065 g,0.2 mmole) was reacted with aqueous sodium hydroxide in the same manneras in example 2. The product was precipitated from the basic reactionmixture with acetic acid, filtered and washed with water to give3,9-diaminobenzo[f]quinazolin-1(2H)-one as a tan solid. (0.04 g, 84%) ¹HNMR (DMSO-d₆, 300 MHz) δ: 5.54 (br s, 2H, NH₂); 6.35 (br s, 2H, NH₂);6.80 (dd, J=8.5, 2.3 Hz, 1H, Ar); 6.87 (d, J=8.6 Hz, 1H, Ar); 7.52 (d,J=8.6 Hz, 1H, Ar); 7.73 (d, J=8.6 Hz, 1H, Ar); 8.73 (s, 1H, Ar); 10.91(br s, 1H, NH).

The following compounds were prepared by catalytic reduction of theN-pivalamide derivatives of the corresponding nitro-substitutedcompounds as described in the above example:

X ¹H NMR (200 MHz)^(a) in DMSO-d₆ (δ) 7-NH₂ 6.59(br s, 4H, 2NH₂);6.65(d, J=7.6Hz, 1H, Ar); 7.12(d, J=9.2Hz, 1H, Ar); 7.25(t, J=8.0Hz, 1H,Ar); 8.23(d, J= 9.2Hz, 1H, Ar); 8.86(d, J=8.4Hz, 1H, Ar). 8-NH₂ 5.26(brs, 2H, NH₂); 6.25(s, 2H, NH₂); 6.85(d, J=2.3Hz, 1H, Ar); 6.96(dd, J=9.0,2.3Hz, 1H, Ar); 7.13(d, J= 8.8Hz, 1H, Ar); 7.69(d, J=8.8Hz, 1H, Ar);9.31(d, J= 9.0Hz, 1H, Ar); 10.9(br s, 1H, NH). 9-NH₂-5,6- 2.40-2.64(m,4H, CH₂CH₂); 4.71(br s, 2H, NH₂); 6.25 dihydro^(a) (dd, J=7.8, 2.2Hz,1H, Ar); 6.53(br s, 2H, NH₂); 6.75(d, J=7.8Hz, 1H, Ar); 7.75(d, J=2.4Hz,1H, Ar); 10.84(br s, 1H, NH). 10-NH₂ 6.25(br s, 2H, NH₂); 6.55(s, 2H,NH₂); 6.88(dd, J=7.4, 1.4Hz, 1H, Ar); 7.07-7.25(m, 3H, Ar); 7.86(d,J=8.9Hz, 1H, Ar); 11.28(br s, 1H, NH). 7-NH₂-8-F^(b) 5.63(br s, 2H,NH₂); 6.47(br s, 2H, NH₂); 7.18(d, J= 9.3Hz, 1H, Ar); 7.29(t, J=10.3Hz,1H, Ar); 8.28(d, J= 9.3Hz, 1H, Ar); 8.92(dd, J=9.3, 5.4Hz, 1H, Ar);11.06(br s, 1H, NH). 8-F-10-NH₂ ^(b) 7.18(dd, J=11.4, 3.0Hz, 1H, Ar);7.38(dd, J=8.8, 2.3Hz, 1H Ar); 7.52(d, J=8.8Hz, 1H, Ar); 8.14(br s, 2H,NH₂); 8.19(d, J=8.7Hz, 1H, Ar). 8,10-(NH₂)2^(b) 7.15(d, J=2.1Hz, 1H,Ar); 7.18(d, J=2.6Hz, 1H, Ar); 7.44(d, J=9.2Hz, 1H, Ar); 7.98(br s, 2H,NH₂); 8.10(d, J=9.2Hz, 1H, Ar). ^(a)The starting material wasN-(8-bromo-1,2,5,6-tetrahydro-9-nitro-1-oxobenzo[f]quinazolin-3-yl)pivalamide.^(b)The product was isolated as the hydrochloride salt by treating asolution of the compound in methanol with an excess of concentratedhydrochloric acid followed by evaporation of the solvent.

All compounds gave elemental analyses consistent with the indicatedstructures.

EXAMPLE 13 3,8-Diamino-5,6-dihydrobenzo[f]quinazolin-1(2H)-one

A suspension of 3-amino-5,6-dihydro-8-nitrobenzo[f]quinazolin-1(2H)-onesulfate monohydrate (2.0 g, 5.3 mmoles) and 5% palladium on carbon (10mg) in 1 N HCl (20 ml) was reacted with hydrogen using a Parrhydrogenation apparatus. When uptake of hydrogen ceased, the mixture wasfiltered and the filtrate was evaporated, leaving a white residue whichwas resuspended in water (20 ml) with stirring, and filtered. The crudeproduct was recrystallized from 2 M H₂SO₄ to give, after drying,3,8-diamino-5,6-dihydrobenzo[f]quinazolin-1(2H)-one as a white solid.(1.1 g, 61%) ¹H NMR (DMSO-d₆, 80 MHz) δ: 2.60-2.65 (m, 4H, CH₂CH₂);4.99-5.69 (br s, 2H, NH₂); 6.75-6.79 (m, 4H, NH₂+Ar); 8.24-8.35 (d, J=9Hz, 1H, Ar). Anal. Calculated for C₁₂H₁₂N₄O.H₂SO₄.1/2H₂O: C, 42.98; H,4.51; N, 16.71; S, 9.56. Found: C, 42.95; H, 4.54; N, 16.66; S, 9.57.

EXAMPLE 14 3-Amino-8-bromobenzo[f]quinazolin-1(2H)-one

To a stirred suspension of 3-aminobenzo[f]quinazolin-1(2H)-one (0.56 g,2.65 mmoles) in glacial acetic acid at 60° C. was added dropwise asolution of bromine (0.85 g, 5.3 mmoles) in glacial acetic acid (1.1 ml)over a 20 minute period. When the addition was completed, the mixturewas heated to reflux for 4 hours, and then allowed to cool beforefiltering. The solid was dissolved into 1 N NaOH and reprecipitated withacetic acid, filtered, washed with water and methanol, and dried.

The crude product was derivatized by reaction with pivalic anhydride inthe same manner as in example 2. The resulting N-pivalamide was purifiedby recrystallization from ether, and then reacted with base as describedpreviously. The product was precipitated from aqueous base with aceticacid, filtered, washed with water and dried to give3-amino-8-bromobenzo[f]quinazolin-1(2H)-one as a tan solid. (0.25 g,32%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 6.60 (s, 2H, NH₂); 7.33 (d, J=9.0 Hz,1H, Ar); 7.70 (dd, J=9.2, 2.2 Hz, 1H, Ar); 8.00 (d, J=9.0 Hz, 1H, Ar);8.13 (d, J=2.2 Hz, 1H, Ar); 9.55 (d, J=9.2 Hz, 1H, Ar); 11.22 (s, 1H,NH). Anal. Calculated for C₁₂H₈BrN₃O.1/2H₂O: C, 48.18; H, 3.03; N,14.05. Found: C, 48.22; H, 3.04; N, 14.07.

EXAMPLE 15 3,8-Diamino-7,9-dibromobenzo[f]quinazolin-1(2H)-one

To a stirred mixture of3,8-diamino-5,6-dihydrobenzo[f]quinazolin-1(2H)-one sulfate hemihydrate(0.5 g, 1.5 mmoles) in acetic acid (15 ml) at 60° C. under a nitrogenatmosphere was added bromine (1 ml) in one portion. The temperature wasraised to 90° C. for 1 hour and then cooled before pouring onto ice (40g). After the mixture had stood for 10 minutes the precipitate wasfiltered, washed with water and recrystallized from 2 M H₂SO to give3,8-diamino-7,9-dibromobenzo[f]quinazolin-1(2H)-one as an off-whitesolid. (0.2 g, 27%) ¹H NMR (DMSO-d₆, 80 MHz) δ: 5.0-6.5 (br s, 2H, NH₂);7.53-7.65 (d, J=9 Hz, 1H, Ar); 8.23-8.27 (br s, 3H, NH₃ ⁺); 8.30-8.42(d, J=9 Hz, 1H, Ar); 9.78 (s, 1H, Ar).

EXAMPLE 16 3-(Benzylamino)-7-bromobenzo[f]quinazolin-1(2H)-one

A. N-(7-Bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

The title compound was prepared in three steps from5-bromo-3,4-dihydro-2-hydroxy-1-naphthoate using the same routedescribed for the analogous 9-bromo compound, without significantmodification. The final product was purified by trituration with water,followed by filtration and drying to giveN-(7-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide as a paleyellow solid. (Overall yield was 49%). ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.27(s, 9H, t-butyl); 7.62 (t, J=8.1 Hz, 1H, Ar); 7.71 (d, J=9.2 Hz, 1H,Ar); 7.95 (dd, J=7.6, 1.0 Hz, 1H, Ar); 8.48 (d, J=9.3 Hz, 1H, Ar); 9.81(d, J=8.6 Hz, 1H, Ar); 11.29 (br s, 1H, NH); 12.3 (br s, 1H, NH).

B. 3-(Benzylamino)-7-bromobenzo[f]quinazolin-1(2H)-one

A mixture ofN-(7-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.3 g,0.8 mmole) and benzylamine (10 ml) was stirred and heated at refluxunder a nitrogen atmosphere for 18 hours. The cooled reaction mixturewas then mixed with 4 volumes of ether to cause precipitation of theproduct. The precipitate was filtered and recrystallized from methanolto give 3-(benzylamino)-7-bromobenzo-[f]quinazolin-1(2H)-one as anoff-white solid. (0.11 g, 37%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 4.62 (d,J=5.7 Hz, 2H, CH₂); 7.02 (m, 1H, benzyl-NH); 7.20-7.55 (m, 7H, Ar); 7.79(dd, J=7.5, 1.1 Hz, 1H, Ar); 8.30 (d, J=9.2 Hz, 1H, Ar); 9.74 (d, J=8.6Hz, 1H, Ar); 11.2 (br s, 1H, pyr-NH).

In a similar manner, the following compounds were prepared from theindicated precursors

X ¹H NMR (200 MHz) in DMS0-d₆ (δ) Elemental Analysis 7-F^(a) 4.61(d, J =6 Hz, 2H, CH²); 6.96(br t, J = 6 Hz, 1H, pyr-NH-benzyl); 7.20-7.48(m,7H, Ar); 7.58(ddd, J = 8, 8, 6 Hz, 1H, Ar); 8.17(d, J = 9 Hz, 1H, Ar);9.43(d, J = 10 Hz, 1H, Ar); 11.20(br s, 1H, NH). 9-Cl^(b) 4.61(d, J = 6Hz, 2H, CH₂); 6.95(br t, J = 6 Hz, 1H, pyr-NH-benzyl); 7.18-7.43(m, 6H,Ar); 7.46(dd, J = 9, 2 Hz, 1H, Ar); 7.92(d, J = 9 Hz, 1H, Ar); 8.05(d, J= 9 Hz, 1H, Ar); 9.68(d, J = 2 Hz, 1H, Ar); 11.24(br s, 1H, NH).^(a)Prepared from the corresponding N-pivalamide. ^(b)Prepared from thecorresponding 3-amino compound.

The following additional examples of compounds bearing modifications ofthe 3-amino group were prepared as described.

N-(9-Bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)formamide

To a solution of mixed anhydride prepared by adding 96% formic acid (10ml) to acetic anhydride (20 ml) and stirring 45 minutes, was added2-amino-9-bromobenzo-[f]quinazolin-1(2H)-one (0.20 g, 0.69 mmol). Thesuspension was heated until homogeneous, and the solution stirred 45minutes without additional heat and then 15 minutes with warming untilTLC (methanol:methylene chloride (1:9)) indicated complete reaction. Thesolution was chilled briefly in an ice bath and then allowed to stand atroom temperature for 45 minutes. The resulting crystals were filtered,washed with water, and dried at 95° C. under reduced pressure to giveN-(9-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)formamide (0.135 g)as a white solid. ¹H NMR (DMSO-d₆, 200 MHz) δ: 7.55 (d, J=9 Hz, 1H, Ar),7.73 (dd, J=9 Hz, 1H, Ar), 7.97 (d, J=9 Hz, 1H, Ar); 8.22 (d, J=9 Hz,1H, Ar); 8.97 (br s, 1H, CHO); 9.89 (s, 1H, Ar), 10.75 (br s, 1H, CONH),11.89 (brs, 1H, NH).

5,6-Dihydro-3-(methylamino)benzo[f]quinazolin-1(2H)-one

Methyl 3,4-dihydro-2-hydroxy-1-naphthoate was reacted withmethylguanidine in the same manner as for the analogous reaction usingguanidine (example 1) to obtain5,6-dihydro-3-(methylamino)benzo[f]quinazolin-1(2H)-one. ¹H NMR(DMSO-d₆, 200 MHz) δ: 2.52-2.64 (m, 2H, CH₂), 2.68-2.82 (m, 2H, CH₂),2.81 (d, J=5 Hz, 3H, NCH₃), 6.54 (br s, 1H, C³NH), 7.02 (ddd, J=8, 8, 2Hz, 1H, Ar), 7.07-7.18 (m, 2H, Ar), 8.42 (dd, J=8, 2 Hz, 1H, Ar), 10.98(br s, 1H, N²H).

All compounds gave elemental analyses consistent with the indicatedstructures.

EXAMPLE 17 3-Amino-9-ethynylbenzo[f]quinazolin-1(2H)-one

A.N-(1,2-Dihydro-1-oxo-9-(2(trimethylsilyl)ethynyl)benzo[f]quinazolin-3-yl)pivalamide

A suspension of 3-amino-9-bromobenzo[f]quinazolin-1(2H)-one (0.99 g, 3.4mmol) in pivalic anhydride (10 ml) was heated to reflux. The resultingsolution was stirred at this temperature for 10 minutes and thenconcentrated in vacuo. The solid was resuspended intriethylamine:acetonitrile (1:3, 80 ml) and triphenyl phosphine (0.53 g,2.0 mmol), trimethylsilylacetylene (3.0 ml, 21 mmol) (Aldrich), and Pd(OAc)₂ (0.23 g, 1.0 mmol) were added and the reaction mixture wasstirred for 25 hours at 65° C. After cooling, the resulting solid wasfiltered and washed with diethyl ether to give crude product (0.84 g).This was combined with material (0.83 g) from a similar reaction andpurified by chromatography on silica gel eluting with ethylacetate-methylene chloride (1:99) to giveN-(1,2-dihydro-1-oxo-9-(trimethylsilylethynyl)benzo[f]quinazolin-3-yl)pivalamide(0.25 g). ¹H NMR (DMSO-d₆, 200 MHz) δ: 0.28 (s, 9H, Si(CH₃)₃), 1.27 (s,9H, t-butyl), 7.56 (d, J=9 Hz, 1H, Ar), 7.60 (dd, J=8, 1 Hz, 1H, Ar),8.00 (d, J=8 Hz, 1H, Ar), 8.22 (d, J=9 Hz, 1H, Ar), 9.81 (s, 1H, Ar),11.27 (br s, 1H, N²H), 12.44 (br s, 1H, C³—NH). Anal. Calculated forC₂₂H₂₅N₃O₂Si: C, 67.49; H, 6.44; N, 10.73. Found: C, 67.35; H, 6.48; N,10.65.

B. 3-Amino-9-ethynylbenzo[f]quinazolin-1(2H)-one

A solution ofN-(1,2-dihydro-1-oxo-9-(trimethylsilylethynyl)benzo[f]quinazolin-3-yl)pivalamide(0.24 g, 0.61 mmol) and K₂CO₃ (0.50 g, 3.6 mmol) in methanol (^(˜)50 ml)was stirred at reflux for 2.5 hours. The solution was then diluted withwater (^(˜)20 ml) acidified with acetic acid, and the resulting solidfiltered and dried at 90° C. under reduced pressure. The solid wasresuspended in ethanol (^(˜)20 ml), filtered, and dried to give3-amino-9-ethynyl benzo[f]quinazolin-1(2H)-one (0.084 g) as a tan solid.¹H NMR (DMSO-d, 200 MHz) δ: 4.26 (s, 1H, ethynylCH), 6.63 (br s, 2H,NH₂), 7.32 (d, J=9 Hz, 1H, Ar), 7.47 (dd, J=8, 2 Hz, 1H, Ar), 7.87 (d,J=8 Hz, 1H, Ar), 8.02 (d, J=9 Hz, 1H, Ar), 9.78 (s, 1H, Ar), 11.34 (brs, 1H, NH). Mass spectrum (CI-CH₄): 236 (M+1, 100%). Anal. Calculatedfor C₁₄H₉N₃O: C, 71.48; H, 3.86; N, 17.86. Found: C, 71.30; H, 3.92; N,17.68.

EXAMPLE 18 3-Amino-9-vinylbenzo[f]quinazolin-1(2H)-one

A solution of 3-amino-9-ethynyl benzo[f]quinazolin-1(2H)-one (0.19 g,0.18 mmol) in pivalic anhydride (4 ml) was stirred at reflux for 10minutes and then concentrated in vacuo. A solution of the residual solidand Lindlar catalyst (50 mg) in ethanol (50 ml) was shaken underhydrogen (^(˜)10 psi) for 30 minutes and then filtered through celiteand concentrated in vacuo. The residue was purified by chromatography onsilica gel eluting with ethyl acetate:hexane (1:4) to giveN-(1,2-dihydro-1-oxo-9-vinylbenzo[f]quinazolin-3-yl)pivalamide. Asolution of the solid in methanol (9 ml) and 1 N NaOH (1 ml) was stirredat reflux for 1.5 hours and, after cooling, was neutralized with aceticacid. The resulting precipitate was filtered and dried at 85° C. underreduced pressure to give 3-amino-9-vinyl benzo[f]quinazolin-1(2H)-one(0.067 g) as a white solid. ¹H NMR (DMSO-d₆, 200 MHz) δ: 5.36 (d, J=12Hz, 1H, vinylCH), 5.94 (d, J=18 Hz, 1H, vinylCH), 6.54 (br s, 2H, NH₂),6.89 (dd, J=18, 12 Hz, 1H, vinylCH), 7.26 (d, J=9 Hz, 1H, Ar), 7.64 (dd,J=8, 2 Hz, 1H, Ar), 7.83 (d, J=8 Hz, 1H, Ar), 7.98 (d, J=9 Hz, 1H, Ar),9.63 (s, 1H, Ar), 11.13 (br s, 1H, NH). Mass spectrum (CI-CH₄): 238(M+1, 100%). Anal. Calculated for C₁₄H₁₁N₃O: C, 70.87; H, 4.67; N,17.71. Found: C, 70.77, H, 4.73; N, 17.66.

EXAMPLE 19 3-Amino-9-ethylbenzo[f]quinazolin-1(2H)-one

A solution of 3-amino-9-vinylbenzo[f]quinazolin-1(2H)-one (0.060 g, 0.25mmol) and 10% palladium on carbon (0.10 g) (Aldrich) in ethanol (200 ml)was shaken under hydrogen (40 psi) for 1 hour and then filtered throughcelite and concentrated in vacuo. The residue was suspended in ethanol,filtered, and dried at 85° C. under reduced pressure to give3-amino-9-ethylbenzo[f]-quinazolin-1(2H)-one (0.039 g) as a white solid.¹N NMR (DMSO-d₆, 200 MHz) δ: 1.26 (t, J=7 Hz, 3H, CH₃), 2.76 (q, J=7 Hz,2H, CH₂), 6.49 (br s, 2H, NH₂), 7.21 (d, J=9 Hz, 1H, Ar), 7.31 (dd, J=8,2 Hz, 1H, Ar), 7.77 (d, J=8 Hz, 1H, Ar), 7.96 (d, J=9 Hz, 1H, Ar), 9.47(s, 1H, Ar), 11.08 (br s, 1H, NH). Mass spectrum (CI-CH₄): 240 (M+1,100%). Anal. Calculated for C₁₄H₁₃N₃O.0.1H₂O: C, 69.75; H, 5.52; N,17.43. Found: C, 69.79; H, 5.53; N, 17.37.

EXAMPLE 203-Amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazoline-8-sulfonamide

A. 3-Amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-8-sulfonylchloride

Chlorosulfonic acid (25 ml, Aldrich), cooled to 5° C. in ice, wasstirred during its addition to3-amino-1,2,5,6-tetrahydro-1-oxo-benzo[f]quinazoline (5 g, 0.025 mole)contained in a beaker immersed in an ice bath. The solution was removedfrom the ice bath, stirred for a further 20 min, then poured onto ice(1000 g). The solid product was removed by filtration, washed withwater, and dried under high vacuum at room temperature. The sulfonylchloride was used without further purification.

D. 3-Amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazoline-8-sulfonamide

3-Amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-8-sulfonyl chloride(1 g) was heated at reflux with concentrated (s.g.=0.9) aqueous ammonia(10 ml) for 10 min. The solution was allowed to cool to roomtemperature, water (10 ml) was added, the gold solid was removed byfiltration, washed well with water, a little ethanol, then dried at 60°C. in vacuo to yield the sulfonamide, (0.703 g, 76%) ¹H NMR (DMSO-d₆,200 MHz) δ: 2.55-2.62 (m, 2H, ArCH₂); 2.80-2.87 (m, 2H, ArCH₂); 6.80 (brs, 2H, NH₂); 7.16 (s, 2H, NH₂); 7.54-7.59 (m, 2H, Ar); 8.56 (d, J=9 Hz,1H, Ar); 11.02 (br s, 1H, NH). Mass spectrum (CI) 293: (M+1, 100%).

The following compounds were similarly prepared.

3-Amino-N,N-diethyl-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazoline-8-sulfonamide

(0.118 g, 70.7%), by heating the acid chloride (0.15 g) with a 25%aqueous solution of diethylamine (3 ml). ¹H NMR (DMSO-d₆, 200 MHz) δ:1.04 (t, J=7.1 Hz, 6H, CH₂ CH ₃); 2.53-2.62 (m, 2H, ArCH₂); 2.80-2.90(m, 2H, ArCH₂); 3.12 (q, J=7.1 Hz, 4H, CH₂ CH ₃); 6.85 (br s, 2H, NH₂);7.49-7.55 (m, 2H, Ar); 8.59 (d, J=9 Hz, 1H, Ar); 10.8-11.3 (v br s, 1H,NH). Mass spectrum (CI): 349 (M+1, 4.29%).

3-Amino-1,2,5,6-tetrahydro-1-oxo-N-(prop-2-vnyl)benzo[f]quinazoline-8-sulfonamide

(0.105 g, 23.3%), by heating the acid chloride (0.4 g) withpropargylamine (5 ml), evaporating the mixture in vacuo, triturating theresidue with water (3 ml), and crystallizing the solid product fromethanol. ¹H NMR (DMSO-d₆, 200 MHz) δ: 2.50-2.62 (m, 2H, ArCH₂);2.80-2.88 (m, 2H, ArCH₂); 3.07 (t, J=2.51 Hz, 1H, propargylCH);3.62-3.66 (m, 2H, propargylCH₂); 6.79-6.85 (br s, 2H, NH₂); 7.52-7.57(m, 2H, Ar); 7.93 (t, J=5.86 Hz, 1H, SO₂NH); 8.59 (d, J=8.94 Hz, 1H,Ar); 11.02-11.04 (br s, 1H, NH). Mass spectrum (CI): 331 (M+1, 100%).

3-Amino-1,2,5,6-tetrahydro-1-oxo-N,N-bis(prop-2-vnyl)benzo[f]quinazoline-8-sulfonamide

(0.089, 15.5%) from the acid chloride (0.4 g) and dipropargylamine (5ml) as above. ¹H NMR (DMSO-d₆, 200 MHz) δ: 2.59-2.66 (m, 2H, ArCH₂);2.83-2.91 (m, 2H, ArCH₂); 3.24 (t, J=2.3 Hz, 2H, propargylCH); 4.06 (d,J=2.3 Hz, 4H, propargylCH₂); 7.09-7.14 (br s, 2H, NH₂); 7.56-7.60 (m,2H, Ar); 8.60 (d, J=9.14 Hz, 1H, Ar). Mass spectrum (CI): 369 (M+1,72%).

All compounds gave elemental analyses consistent with the indicatedstructures.

EXAMPLE 211,2,5,6-Tetrahydro-3-methyl-1-oxobenzo[f]quinazoline-9-sulfonamide

A.1,2,5,6-Tetrahydro-3-methyl-1-oxobenzo[f]quinazolin-9-sulfonylchloride

1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]quinazoline (5 g, 0.024 mole)was added to chlorosulfonic acid (50 ml, Aldrich) and stirred for 12hours at room temperature. The reaction mixture was poured over ice (750g), and the dark brown solid collected by filtration. The solid waswashed with water, suspended in water (500 ml), and the pH of thesuspension adjusted to 5.00 by addition of sodium bicarbonate. Thesuspension was filtered, the product washed with H₂O and dried underhigh vacuum at room temperature to give1,2,5,6-tetrahydro-3-methyloxobenzo[f]quinazolin-9-sulfonyl chloride asa light brown solid (3.054 g, 41%). ¹H NMR (DMSO-d₆, 300 MHz) δ: 2.60(s, 3H, CH₃); 2.90 (s, 4H, ArCH₂); 7.22 (d, J=9 Hz, 1H, Ar); 7.53 (d,J=9 Hz, 1H, Ar); 8.75 (s, 1H, Ar).

B. 1,2,5,6-Tetrahydro-3-methyl-1-oxobenzo[f]quinazoline-9-sulfonamide

(0.48 g, 51%), was prepared by the action of concentrated aqueousammonia on the foregoing acid choride (1.0 g) essentially as describedfor the corresponding 3-amino compound. Mp>240° C. ¹H NMR (DMSO-d₆, 300MHz) δ: 2.33 (s, 3H, CH₃), 2.74 (t, J=8 Hz, ArCH₂), 2.92 (t, J=8 Hz,ArCH₂), 7.29 (s, 2H, NH₂), 7.41 (d, J=8 Hz, 1H, Ar), 7.64 (dd, J=8, 2Hz, 1H, Ar), 9.10 (d, J=2 Hz, 1H, Ar), 12.71 (br s, 1H, NH). AnalCalculated for C₁₃H₁₃N₃O₃S.3/20H₂O: C, 53.11; H, 4.56; N, 14.29; S,10.90. Found: C, 53.04; H, 4.53; N, 14.28; S, 10.90.

The following compounds were also prepared from1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]quinazolin-9-sulfonyl chlorideby procedures essentially similar to those described above for thecorresponding 3-amino compounds.

N,N-Diethyl-1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]quinazoline-9-sulfonamide

(50%), M.P.=249-251° C. ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.05 (t, J=7 Hz,6H, amideCH₃ s), 2.32 (s, 3H, C³—CH₃), 2.69-2.77 (m, 2H, ArCH₂),2.88-2.96 (m, 2H, ArCH₂), 3.15 (q, J=7 Hz, 2H, amideCH₂'s), 7.40 (d, J=8Hz, 1H, Ar)), 7.57 (dd, J=8, 2 Hz, 1H, Ar), 9.05 (d, J=2 Hz, 1H, Ar),12.61 (br s, 1H, NH). Mass spectrum (CI-CH₄): 348 (M+1, 100%). Anal.Calculated for C₁₇H₂₁N₃O₃S: C, 58.77; H, 6.09; N, 12.09; S, 9.23. Found:C, 58.59; H, 6.15; N, 12.03; S, 9.16.

1,2,5,6-Tetrahydro-N,N, 3-trimethylbenzo[f]quinazoline-9-sulfonamide

(45%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 2.30 (s, 3H, C³—CH₃), 2.60 (s, 6H,N(CH₃)₂), 2.70-2.79 (m, 2H, ArCH₂), 2.90-2.98 (m, 2H, ArCH₂), 7.46 (d,J=8 Hz, 1H, Ar), 7.53 (dd, J=8, 1.5 Hz, 1H, Ar), 9.00 (d, J=1.5 Hz, 1H,Ar), 12.62 (br s, 1H, NH). Mass spectrum (CI-CH₄) 320 (M+1, 100%). Anal.Calculated for C₁₅H₁₇N₃O₃S: C, 56.41; H, 5.36; N, 13.16; S, 10.04. FoundC, 56.35; H, 5.38; N, 13.09; S, 10.03.

EXAMPLE 223-Amino-N,N-diethyl-1,2-dihydro-1-oxobenzo[f]quinazoline-9-sulfonamide

A.3-Amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)one-9-sulfonylchloride

Chlorosulfonic acid (100 g) was added to3-amino-8-bromo-5,6-dihydro-benzo[f]quinazolin-1(2H)-one (5.20 g, 17.8mmole) and the solution stirred overnight at room temperature. Thereaction mixture was poured over ice, the collected solid washed withwater, and dried under high vacuum to give3-amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonylchloride (7.25 g, 90%). ¹H NMR (DMSO-d₆, 200 MHz) δ: 2.67-2.75 (m, 2H,ArCH₂), 2.81-2.88 (m, 2H, ArCH₂), 7.43 (s, 1H, Ar), 8.23 (br s, 2H,NH₂), 8.91 (s, 1H, Ar), 9.90-10.50 (v br s, 1H, NH). Anal Calculated forC₁₂H₉BrClN₃O₃S1/2H₂O.9/20H₂SO₄: C, 32.48; H, 2.48; N, 9.47; S, 10.46.Found: C, 32.68; H, 2.37; N, 9.20; S, 10.40.

B.3-Amino-8-bromo-N,N-diethyl-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonamide

3-Amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonylchloride(1.10 g, 2.8 mmole) and diethylamine (5 ml) were dissolved in water (15ml) and heated to reflux for 30 minutes. The reaction mixture was cooledto room temperature and neutralized with dilute acetic acid. Thecollected precipitate was suspended in boiling methanol, the suspensionallowed to cool, and the solid filtered off and dried under high vacuumto give3-amino-8-bromo-N,N-diethyl-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonamide(0.708 g, 59%). ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.07 (t, J=7 Hz, 6H,ethylCH₃), 2.54-2.62 (m, 2H, ArCH₂), 2.81-2.88 (m, 2H, ArCH₂), 3.26 (q,J=7 Hz, 4H, ethylCH₂), 6.83 (br s, 2H, NH₂), 7.60 (s, 1H, Ar), 9.13 (s,1H, Ar), 10.95 (br s, 1H, NH). Anal Calculated for C₁₆H₁₉BrN₄O₃S: C,44.97; H, 4.48; Br, 18.70; N, 13.11; S, 7.50. Found: C, 44.90; H, 4.49;Br, 18.65; N, 13.03; S, 7.57.

C.3-Amino-8-bromo-N,N-diethyl-1,2-dihydro-1-oxobenzo[f]quinazoline-9-sulfonamide

3-Amino-8-bromo-N,N,-diethyl-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonamide(0.165 g, 0.39 mmole) was suspended in pivalic anhydride (5 ml)(Aldrich) and heated under nitrogen until dissolved. The solution washeated under reflux for 10 minutes, cooled, and the pivalic anhydrideremoved in vacuo. The dried solid was dissolved in benzene (20 ml),pyridine (0.05 ml) added, and the solution heated to boiling undernitrogen. N-Bromosuccinimide (0.07 g, 0.47 mmole) was added, and themixture refluxed for an additional 6 hours. The reaction mixture wascooled to room temperature, solvent removed in vacuo, and the solidresidue crystallized from methanol. The pivalamide (0.105 g) wasdissolved in methanol (2 ml), 1N NaOH (4 ml) added, and the solutionheated to reflux under nitrogen for 1 hour. The cooled reaction mixturewas neutralized with dilute acetic acid, the crystals collected byfiltration and suspended in methanol. The collected crystals were driedin vacuo to give3-amino-8-bromo-N,N-diethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-9-sulfonamide(0.055 g, 33%). Mp>250° C. ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.10 (t, J=7 Hz,6H, ethylCH₃), 3.38 (q, J=7 Hz, 4H, ethylCH₂), 6.78 (br s, 2H, NH₂),7.47 (d, J=9 Hz, 1H, Ar), 8.09 (d, J=9 Hz, 1H, Ar), 8.40 (s, 1H, Ar),10.30 (s, 1H, Ar), 11.32 (br s 1H, NH). Anal Calculated forC₁₆H₁₇BrN₄O₃S: C, 45.19; H, 4.03; Br, 18.79; N, 13.17; S, 7.54. Found:C, 45.10; H, 4.03; Br, 18.74; N, 13.07; S, 7.56.

EXAMPLE 233-Amino-N,N,-diethyl-1,2-dihydro-1-oxobenzo[f]quinazoline-9-sulfonamide

A.N-(9-((Diethylamino)sulfonyl)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamideandN-(9-((Diethylaminosulfonyl)-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

3-Amino-8-bromo-N,N-diethyl-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonamide(0.43 g, 1 mmole) was suspended in methanol (200 ml). 10% Palladium oncarbon (0.60 g) was added to the suspension and the mixture was shakenunder a hydrogen atmosphere at 23 psi for 3 hours. Methanol (750 ml) wasadded, and the mixture refluxed until the solid dissolved. The hotsolution was filtered through celite. The celite and catalyst werewashed by heating under reflux in methanol (500 ml) and the suspensionfiltered through fresh celite. Methanol was removed from the combinedfiltrates and the solid heated under reflux with pivalic anhydride (8ml, Aldrich) under nitrogen for 30 minutes. The reaction mixture wasevaporated to dryness, the residue applied to a silica column, andeluted with methanol/methylene chloride (1:199). The main fractionsrepresented the title compounds;

N-(9-((diethylamino)sulfonyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

(0.073 g, 17%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.06 (t, J=7 Hz, 6H,ethylCH₃), 1.27 (s, 9H, t-butyl) 3.23 (q, J=7 Hz, 4H, ethylCH₂), 7.70(d, J=9 Hz, 1H, Ar), 7.91 (dd, J=8, 2 Hz, 1H, Ar), 8.22 (d, J=8 Hz, 1H,Ar), 8.35 (d, J=9 Hz, 1H, Ar), 10.22 (d, J=2 Hz, 1H, Ar), 11.31 (br s,1H, NH), 12.41 (br s, 1H, NH) and

N-(9-((diethylamino)sulfonyl]-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-3-yl)-pivalamide

(0.074 g, 17%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.05 (t, J=7 Hz, 6H,ethylCH₃), 1.24 (s, 9H, t-butyl), 2.73-2.80 (m, 2H, ArCH₂), 2.91-2.99(m, 2H, ArCH₂), 3.14 (q, J=7 Hz, 4H, ethylCH₂) 7.41 (d, J=8 Hz, 1H, Ar),7.56 (dd, J=8, 2 Hz, 1H, Ar), 8.98 (d, J=2 Hz, 1H, Ar), 11.32 (br s, 1H,NH), 12.19 (br s, 1H, NH).

B.3-Amino-N,N-diethyl-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonamide

N-(9-((diethylamino)sulfonyl)-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

(0.074 g, 0.17 mmole) was dissolved in a mixture of methanol (2 ml) and1N NaOH (4 ml) and heated to reflux under nitrogen for 30 minutes. Thecooled reaction mixture was neutralized with dilute acetic acid, theprecipitate collected by filtration, washed with methanol and dried invacuo at 95° C. to give the free amine, (0.031 g, 52%). Mp>250° C. ¹HNMR (DMSO-d₆, 200 MHz) δ: 1.05 (t, J=7 Hz, 6H, ethylCH₃), 2.53-2.62 (m,2H, ArCH₂), 2.79-2.89 (m, 2H, ArCH₂), 3.13 (q, J=7 Hz, 4H, ethylCH₂),6.79 (br s, 2H, NH₂), 7.32 (d, J=8 Hz, 1H, Ar), 7.41 (dd, J=2,8 Hz, 1H,Ar), 8.93 (s, 1H, Ar), 10.93 (br s, 1H, NH). Anal. Calculated forC₁₆H₂₀N₄O₃S: C, 55.16; H, 5.79; N, 16.08. Found: C, 55.10; H, 5.83; N,16.00.

C. Similarly prepared from the corresponding pivalamide was

3-Amino-N,N,-diethyl-1,2-dihydro-1-oxobenzo[f]quinazoline-9-sulfonamide

(0.045 g, 76%). Mp>250° C. ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.05 (t, J=7 Hz,6H, ethylCH₃), 3.21 (q, J=7 Hz, 4H, ethylCH₂), 6.69 (br s, 2H, NH₂),7.44 (d, J=9 Hz, 1H, Ar), 7.74 (dd, J=8, 2 Hz, 1H, Ar), 8.07 (d, J=8 Hz,1H, Ar), 8.13 (d, J=9 Hz, 1H, Ar), 10.14 (s, 1H, Ar), 11.24 (br s, 1H,NH). Anal. Calculated for C₁₆R₁₈N₄O₃S.1/4H₂O: C, 54.77; H, 5.31; N,15.97. Found: C, 54.75; H, 5.16; N, 15.93.

EXAMPLE 24N-(4-((3-Amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-8-yl)sulfonamido)benzoyl)-L-glutamicacid

A.Diethyl-N-(4-((3-amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-8-yl)sulfonamido)benzoyl)-L-glutamate

N-(4-Aminobenzoyl)-L-glutamic acid diethyl ester (3.2 g, 0.01 mole)(Aldrich) and3-amino-1,2,5,6-tetrahydro-1-oxobenzo[f]-quinazolin-8-sulfonyl chloride(0.62 g, 0.002 mole)were fused at 150° C. until a clear melt wasobtained (10 min). A solution of the crude product in methylene chloridewas subjected to chromatography on silica, eluting withmethanol:methylene chloride (1:4). Fractions containing the product wereevaporated, the residue recrystallized from ethanol and dried under highvacuum to yield the diethyl ester (0.48 g, 40.2% based on sulfonylchloride). ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.00-1.2 (overlapping t, 6H, CH₂CH ₃); 1.88-2.15 (m, 2H, gluCH₂); 2.32-2.45 (m , 2H, gluCH₂); 2.45-2.60(m, 2H, ArCH₂); 2.72-2.86 (m, 2H, ArCH₂); 3.92-4.12 (overlapping q, 4H,CH₂ CH ₃); 4.26-4.11 (m, 1H, gluCH); 6.66-7.00 (br s, 2H, NH₂); 7.16 (d,J=8.6 Hz, 2H, Ar); 7.52-7.63 (m, 2H, Ar); 7.71 (d, J=8.6 Hz, 1H, Ar);8.54 (d, J=7.2 Hz, 1H, gluNH); 8.54 (d, J=9 Hz, 1H, Ar); 10.55 (br s,1H, SO₂NH); 11.03 (br s, 1H, N²H). Anal Calculated for C₂₈H₃₁N₅O₈S: C,56.27; H, 5.23; N, 11,72; S, 5.36. Found: C, 56.19; H, 5.24; N, 11.63;S, 5,41.

B.N-(4-((3-Amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-8-yl)sulfonamido)benzoyl)-L-glutamicacid

Diethyl-N-(4-((3-amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-8-yl)sulfonamido)benzoyl)-L-glutamate(0.15 g, 7.6 mmole) was dissolved in a mixture of 2N-NaOH (3 ml) andethanol (6 ml) and the solution stored at room temperature for 14 hours.The ethanol was evaporated and the pH of the solution was adjusted to 2with 1 N HCl. The solid was collected by filtration, washed with waterand dried at 60° C. under vacuum. The product was crystallized once fromethanol to yield a white solid (0.12 g, 85%). ¹H NMR (DMSO-d₆, 200 MHz)δ: 1.75-2.18 (m, 2H, gluCH₂); 2.20-2.40 (m, 2H, gluCH₂); 2.54-2.64 (m,2H, ArCH₂); 2.70-2.89 (m, 2H, ArCH₂); 4.23-4.40 (m, 1H, gluCH);6.70-7.08 (br s, 2H, NH₂); 7.16 (d, J=8.64 Hz, 2H, Ar); 7.56-7.61 (m,2H, Ar); 7.72 (d, J=8.63 Hz, 2H, Ar); 8.42 (d, J=7.81 Hz, 1H, gluNH);8.54 (d, J=8.99 Hz, 1H, Ar); 10.55 (s, 1H, SO₂NH); 10.91-11.24 (br s,1H, N²H); 11.98-12.63 (v br s, 2H, CO₂H); shows presence of water andEtOH. Anal Calculated for C₂₄H₂₃N₅O₈S.3/5H₂O.1/5EtOH: C, 52.19; H, 4.56;N, 12.47; S, 5.71. Found: C, 52.24; H, 4.61; N, 12.51; S, 5.76.

Similar reaction of diethyl N-(4-(prop-2-ynylaminobenzoyl)-L-glutamate(T. R. Jones et al., U.S. Pat. No. 4,564,616, 1986) with3-amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-8-sulfonyl chlorideand subsequent hydrolysis of the diester intermediate gaveN-(4-(((3-amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-8-yl)sulfonyl(prop-2-ynyl)-amino)benzoyl)-L-glutamicacid (8.3% from sulfonyl chloride) ¹H NMR (DMSO-d₆, 200 MHz) δ:1.82-2.20 (m, 2H, gluCH₂); 2.30-2.38 (m, 2H, gluCH₂); 2.56-2.65 (m, 2H,ArCH₂); 2.83-2.87 (m, 2H, ArCH₂); 3.23 (t, J=2 Hz, 1H, propynylCH);4.34-4.40 (m, 1H, gluCH); 4.53 (d, J=2 Hz, 2H, propynylCH₂); 7.03 (br s,2H, NH₂); 7.29 (d, J=8.6 Hz, 2H, Ar); 7.37 (dd, J=2.5 Hz, 8.6 Hz, 1H,Ar); 7.45 (d, J=2.5 Hz, 1H, Ar); 7.83 (d, J=8.6 Hz, 2H, Ar); 8.56 (d,J=8.6 Hz, 1H, Ar); 8.64 (d, J=7.8 Hz, 1H, gluNH); 10.94-11.56 (v br s,1H, N²H); 11.80-12.90 (v br s, 1H, CO₂H); shows presence of H₂O. AnalCalculated for C₂₇H₂₅N₅O₈S.23/10H₂O: C, 52.22; H, 4.80; N, 11.28. Found:C, 52.30; H, 4.61; N, 11.14.

EXAMPLE 25

N-(4-((3-amino-9-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-8-yl)sulfonamido)benzoyl)-L-glutamicacid was prepared from 3-amino-9-bromo-1,2-dihydro-1-oxobenzoquinazoline(6 g) essentially as described above; yields and analytical data on theproduct and intermediates are given below.

A.3-Amino-9-bromo-1,2-dihydro-1-oxobenzo[f]quinazoline-8-sulfonylchloride

(3 g, 36%). ¹H NMR (DMSO-d₆, 200 MHz) δ: 7.59 (d, J=9 Hz, 1H, Ar), 8.44(d, J=8 Hz, 1H, Ar), 8.54 (s, 1H, Ar), 9.75 (s, 1H, Ar), 11.30 (v br s,H₂O+exchangeable H's).

B. DiethylN-(4-((amino-9-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-8-yl)sulfonamidobenzoyl)-L-glutamate

(0.91 g, 17%). Mp>240° C. ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.08 (t, J=7 Hz,3H, esterCH₃), 1.11 (t, J=7 Hz, 3H, esterCH₃), 1.72-2.12 (m, 2H,glu-CH₂), 2.34 (t, J=7 Hz, glu-CH₂), 3.97 (q, J=7 Hz, 2H, esterCH₂),4.02 (q, J=7 Hz, 2H, esterCH₂), 4.24-4.36 (m, 1H, glu-CH), 6.84 (br s,2H, NH₂), 7.17 (d, J=9 Hz, 2H, Ar), 7.39 (d, J=9 Hz, 1H, Ar), 7.66 (d,J=8 Hz, 2H, Ar), 8.26 (d, J=9 Hz, 1H, Ar), 8.47 (d, J=7 Hz, 1H, NH),8.76 (s, 1H, Ar), 9.95 (s, 1H, Ar), 11.01 (s, 1H, NH), 11.39 (s, 1H,NH). Anal Calculated for C₂₈H₂₈BrN₅O₈S:1/2H₂O C, 49.20; H, 4.28; Br,11.69; N, 10.25; S, 4.69. Found: C, 49.19; H, 4.23; Br, 11.66; N, 10.30;S, 4.71.

C.N-(4-((3-Amino-9-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-8-yl)sulfonamido)benzoyl)-L-glutamicacid

(0.68 g, 79%). Mp=238-242° C. ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.72-2.07 (m,2H, glu-CH₂), 2.25 (t, J=7 Hz, glu-CH₂), 4.24-4.29 (m, 1H, glu-CH), 6.65(br s, 2H, NH₂), 7.17 (d, J=9 Hz, 2H, Ar), 7.39 (d, J=9 Hz, 1H, Ar),7.67 (d, J=9 Hz, 2H, Ar), 8.26 (d, J=9 Hz, 1H, Ar), 8.36 (d, J=8 Hz, 1H,NH), 8.78 (s, 1H, Ar), 9.95 (s, 1H, Ar), 11.00 (s, 1H, NH), 11.41 (v brs, 1H, NH), 12.30 (v br s, 2H, OH). Anal Calculated forC₂₄H₂₀BrN₅O₈S.7/5H₂O: C, 44.79; H, 3.57; N, 10.88. Found: C, 44.88; H,3.54; N, 10.75.

EXAMPLE 26N-(4-((3-Amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamicacid

A. DiethylN-(4-(((3-amino-8-bromo-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-9-yl)sulfonyl)amino)benzoyl)-L-glutamate

3-Amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonylchloride (2.00 g, 4.50 mmole) and N-(4-aminobenzoyl)-L-glutamic aciddiethyl ester (7.26 g, 22.5 mmole) (Aldrich) were placed together in atest tube and melted at 175° C. The mixture was heated for 1 hour, 20minutes, the cooled residue suspended in methylene chloride and filteredto remove undissolved solid. The filtrate was evaporated to dryness andthe residue subjected to chromatography on a Waters Prep 500 instrument(silica column, elution with methanol/methylene chloride (1:24)). Thecombined fractions containing product were evaporated and the residuedried under high vacuum. The solid was suspended in boiling ethanol (900ml), the suspension cooled to room temperature and filtered to givediethylN-(4-(((3-amino-8-bromo-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-9-yl)sulfonyl)amino)benzoyl)-L-glutamate(0.794 g, 260). Mp>250° C. ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.12 (t, J=7 Hz,3H, ester-CH₃), 1.14 (t, J=7 Hz, 3H, ester-CH₃), 1.89-2.09 (m, 2H,glu-CH₂), 2.37 (t, J=7 Hz, 2H, glu-CH₂), 2.48-2.59 (m, 2H, ArCH₂),2.77-2.85 (m, 2H, ArCH₂), 3.99 (q, J=7 Hz, 2H, esterCH₂), 4.05 (q, J=7Hz, 2H, esterCH₂), 4.29-4.40 (m, 1H, glu-CH), 6.84 (br s, 2H, NH₂), 7.14(d, J=9 Hz, 2H, Ar), 7.54 (s, 1H, Ar), 7.69 (d, J=9 Hz, 2H, Ar), 8.48(d, J=8 Hz, 1H, NH), 9.37 (s, 1H, Ar), 10.87 (br s, 1H, NH), 11.04 (brs, 1H, NH). Anal. Calculated for C₂₈H₃₀BrN₅O₈S:1/4H₂O C, 49.38; H, 4.51;Br, 11.73; N, 10.20; S, 4.71. Found: C, 49.33; H, 4.40; Br, 11.79; N,10.20; S, 4.74.

B. DiethylN-(4-(((3-amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-9-yl)sulfonyl)amino)benzoyl)-L-glutamate

DiethylN-(4-(((3-amino-8-bromo-1,2,5,6-tetrahydro-1-oxobenzo[f]-quinazolin-9-yl)sulfonyl)amino)benzoyl)-L-glutamate(0.3 g, 0.44 mmole) was dissolved in boiling ethanol (250 ml), thesolution cooled to room temperature, and 10% palladium on carbon (0.20g) added. The mixture was shaken under a hydrogen atmosphere for 35hours. Additional 10% palladium on carbon (0.20 g) was added to thereaction mixture which was then shaken under a hydrogen atmosphere for afurther 15 hours. Ethanol (750 ml) was added, the reaction mixtureheated to reflux, and filtered while hot through celite. Water (33 ml)was added, and the solution neutralized with ammonium hydroxide. Thesolvent was removed in vacuo, the solid suspended in water and themixture neutralized with dilute ammonium hydroxide and dilute aceticacid. The resulting solid was collected by filtration and air dried. Thecrude product was passed through silica gel, eluting withmethanol:methylene chloride. Combined fractions containing product—wereevaporated, and the solid residue suspended in a small amount ofmethanol, filtered, and dried under high vacuum to give the diester(0.095 g). ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.12 (t, J=7 Hz, 3H, CH₃), 1.14(t, J=7 Hz, 3H, CH₃), 1.85-2.15 (m, 2H, glu-CH₂), 2.38 (t, J=7 Hz, 2H,glu-CH₂), 2.48-2.61 (m, 2H, ArCH₂), 2.75-2.87 (m, 2H, Ar CH₂), 4.00 (q,J=7 Hz, 2H, esterCH₂), 4.06 (q, J=7 Hz, 2H, esterCH₂), 4.28-4.42 (m, 1H,glu-CH), 6.78 (br s, 2H, NH₂), 7.16 (d, J=9 Hz, 2H, Ar), 7.27 (d, J=8Hz, 1H, Ar), 7.46 (dd, J=8, 2 Hz, 1H, Ar), 7.70 (d, J=9 Hz, 2H, Ar),8.52 (d, J=7 Hz, 1H, glu-NH), 9.06 (d, J=2 Hz, 1H, Ar), 10.66 (br s, 1H,SO₂NH), 11.03 (br s, 1H, N²H). Anal. Calculated for C₂₈H₃₁N₅O₈S: C,56.27; H, 5.23; N, 11.72. Found: C, 56.35; H, 5.27; N, 11.62.

C.N-(4-((3-Amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamicacid

(0.043 g, 52%) was obtained by hydrolysis of the foregoing diester(0.088 g, 0.15 mmol) in sodium hydroxide as described above. ¹H NMR(DMSO-d₆, 200 MHz) δ: 1.74-2.16 (m, 2H, gluCH₂), 2.29 (t, J=7 Hz, 2H,gluCH₂), 2.48-2.60 (m, 2H, ArCH₂), 2.72-2.86 (m, 2H, ArCH₂), 4.23-4.38(m, 1H, gluCH), 6.78 (br s, 2H, NH₂), 7.16 (d, J=9 Hz, 2H, Ar), 7.26 (d,J=8 Hz, 1H, Ar), 7.45 (dd, J=8, 2 Hz, 1H, Ar), 7.70 (d, J=9 Hz, 2H, Ar),8.42 (br d, J=8 Hz, 1H, gluNH), 9.06 (d, J=2 Hz, 1H, Ar), 10.65 (br s,1H, SO₂NH), 11.05 (br s, 1H, N²H), 12.33 (br s, 2H, CO₂H). Anal.Calculated for C₂₄H₂₃N₅O₈S¹H₂O: C, 51.52; H, 4.50; N, 12.52. Found: C,51.47; H, 4.51; N, 12.52.

EXAMPLE 27N-(4-(((3-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoyl)-L-glutamicacid

A. Methyl4-(((3-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoate

To a solution ofN-(9-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (1.38 g,4.5 mmoles) in dry pyridine (10 ml) was added 4-(chlorosulfonyl)benzoicacid (5.0 g, 22.6 mmoles) at room temperature under a nitrogenatmosphere. After stirring for 3 days, the pyridine was removed underreduced pressure to leave a gummy brown residue which was suspended inwater (30 ml), filtered, washed with water and dried to give4-((N-(1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide)-9-yl)amino)sulfonyl)benzoicacid (1.65 g).

The foregoing material was dissolved in anhydrous 5% HCl/methanol (30ml) and heated to 50° C. with stirring under a nitrogen atmosphere for27 hrs. Upon cooling, a fine precipitate formed which was then filtered,washed with methanol and dried to give methyl4-(((3-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoateas an off-white solid. (0.41 g, 27%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 3.82(s, 3H, OCH₃); 7.36 (dd, J=8.8, 2Hz, 1H, Ar); 7.39 (d, J=8.8 Hz, 1H,Ar); 7.90 (d, J=8.8 Hz, 1H, Ar); 7.98-8.11 (m, 6H, Ar); 8.17 (d, J=9.1Hz, 1H, Ar); 9.33 (d, J=2 Hz, 1H, Ar); 11.00 (br s, 1H, NH). Anal.Calculated for C₂₀H₁₆N₄O₅S.3/5CH₃OH: C, 51.53; H, 4.07; Cl, 7.38; N,11.67; S, 6.68. Found: C, 51.28; H, 3.80; Cl, 7.65; N, 11.90; S, 6.75.

B.4-(((3-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoicacid

A solution of methyl4-(((3-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoate(0.54 g, 1.2 mmoles) in 0.1 N NaOH (30 ml) was stirred at roomtemperature under a nitrogen atmosphere for 19 hrs. After this time, thesolution was acidified (pH 4) with 1 N HCl to cause precipitation of theproduct which was filtered and dried to give4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoicacid as a light brown solid. (0.46 g, 86%) ¹H NMR (DMSO-d₆, 200 MHz) δ:7.28 (d, J=8.9 Hz, 1H, Ar); 7.30 (dd, J=8.3, 2 Hz, 1H, Ar); 7.37 (br s,2H, NH₂); 7.82 (d, J=8.6 Hz, 1H, Ar); 7.95-8.06 (m, 5H, Ar); 9.38 (d,J=2 Hz, 1H, Ar); 10.85 (s, 1H, NH). Anal. Calculated forC₁₉H₁₄N₄O₅.4/5HCl.11/10H₂O: C, 49.68; H, 3.73; N, 12.20. Found: C,49.61; H, 3.78; N, 12.30.

C. DiethylN-(4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoyl)-L-glutamate

To a solution of L-glutamic acid diethyl ester (0.81 g, 4.0 mmoles) and4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoicacid (0.43 g, 0.9 mmoles) in dry dimethylformamide (20 ml) was added1-hydroxybenzotriazole monohydrate (0.43 g, 3.2 mmoles) anddicyclohexylcarbodiimide (0.66 g, 3.2 mmoles). The solution was stirredat room temperature under a nitrogen atmosphere for 20 hrs, after whichtime the solvent was removed under reduced pressure. The residue wasrecrystallized successively from methylene chloride:methanol/9:1 andmethanol to give diethylN-(4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoyl)-L-glutamateas a white solid. (0.215 g, 36%). ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.12 (t,J=7 Hz, 3H, ester-CH₃); 1.15 (t, J=7 Hz, 3H, ester-CH₃); 1.89-2.13 (m,2H, glu-CH₂); 2.40 (t, J=7.6 Hz, 2H, glu-CH₂); 4.00 (q, J=7 Hz, 2H,ester-CH₂); 4.08 (q, J=7 Hz, 2H, ester-CH₂); 6.55 (br s, 2H, NH₂); 7.16(d, J=8.9 Hz, 1H, Ar); 7.23 (dd, J=8.7, 2 Hz, 1H, Ar); 7.73 (d, J=8.7Hz, 1H, Ar); 7.89 (d, J=8.9 Hz, 1H, Ar); 7.96 (m, 4H, Ar); 8.89 (d,J=7.4 Hz, 1H, glu-NH); 9.48 (d, J=2 Hz, 1H, Ar); 10.67 (s, 1H, NH);11.08 (s, 1H, NH). Anal. Calculated for C₂₈H₂₉N₅O₈S: C, 56.46; H, 4.91;N, 11.76; S, 5.38. Found: C, 56.45; H, 4.94; N, 11.75; S, 5.43.

D.N-(4-(((3-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoyl)-L-glutamicacid

A solution of diethylN-(4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoyl)-L-glutamate(0.175 g, 0.3 mmoles) in 1 N NaOH (12 ml) was stirred and heated to 50°C. under a nitrogen atmosphere for 24 hrs. After cooling,the solutionwas acidified (pH 3) with concentrated HCl to cause precipitation of theproduct which was filtered, washed with water and dried to giveN-(4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)-amino)sulfonyl)benzoyl)-L-glutamicacid as an off-white solid. (0.18 g, 99%) ¹H NMR (DMSO-d₆, 300 MHz) δ:1.81-2.13 (m, 2H, glu-CH₂); 2.32 (t, J=7.6 Hz, 2H, glu-CH₂); 4.34 (m,1H, glu-CH); 6.58 (br s, 2H, NH₂); 7.16 (d, J=8.9 Hz, 1H, Ar); 7.22 (dd,J=8.6, 2 Hz, 1H, Ar); 7.74 (d, J=8.7 Hz, 1H, Ar); 7.89 (d, J=9.0 Hz, 1H,Ar); 7.96 (m, 4H, Ar); 8.78 (d, J=7.6 Hz, 1H, glu-NH); 9.49 (d, J=2 Hz,1H, Ar); 10.68 (s, 1H, NH); 11.1 (br s, 1H, NH); 12.3 (br s, 2H,(CO₂H)₂). Anal. Calculated for C₂₄H₂₁N₅O₈S.3H₂O: C, 48.56; H, 4.58; N,11.80; S, 5.40. Found: C, 48.38; H, 4.30; N, 11.69; S. 5.34.

EXAMPLE 28N-(4-((1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamicacid

A.Diethyl-N-(4-((1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamate

N-(4-Aminobenzoyl)-L-glutamic acid diethyl ester (6.06 g, 0.0188 mole)(Aldrich) and1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]-quinazolin-9-sulfonyl chloride(5.84 g, 0.0188 mole) were dissolved in pyridine (55 ml) and thereaction mixture stirred at room temperature for 3.5 hours. The pyridinewas removed in vacuo, the residue washed with water, and the pink solidcollected by filtration. The crude product was dried under high vacuum,then subjected to chromatography on a Waters Prep 500 instrument (silicacartridge, elution with methanol:methylene chloride (1:4). The productwas recrystallized from ethanol and dried under high vacuum to yield thediethyl ester (5.68 g, 51%). ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.14 (t, J=7Hz, 3H, CH₂ CH ₃); 1.16 (t, J=7 Hz, 3H, CH₂ CH ₃); 1.88-2.13 (m, 2H,gluCH₂); 2.32 (s, 3H, CH₃); 2.40 (t, J=8 Hz, 2H, gluCH₂); 2.71 (m, 2H,ArCH₂); 2.89 (m, 2H, Ar-CH ₂); 4.02 (q, J=7 Hz, 2H, CH ₂CH₃); 4.08 (q,J=7 Hz, 2H, CH ₂CH₃); 4.33-4.41 (m, 1H, CH); 7.20 (d, J=9 Hz, 2H, Ar);7.39 (d, 1H, J=8 Hz, Ar); 7.62 (dd, J=8, 2 Hz, Ar); 7.73 (d, J=9 Hz, 2H,Ar); 8.55 (d, J=8 Hz, 1H, gluNH); 9.21 (d, 2 Hz, 1H, Ar); 10.74 (s, 1H,NH); 12.72 (s, 1H, NH). Anal. Calculated for C₂₉H₃₂N₄O₈S.1/10EtOH:3/4H₂OC, 57.05; H, 5.59; N, 9.11; S, 5.22. Found: C, 57.08; H, 5.58; N, 9.15;S, 5.17.

B.N-(4-((1,2,5,6-Tetrahydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamicacid

Diethyl-N-(4-((1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamate(4.53 g, 7.6 mmole) was dissolved in N-NaOH (64 ml) and the solutionstirred at room temperature for 4 hours. The pH of the solution wasadjusted to 3.00 with 1 N HCl, the solid collected by filtration, washedwith water and dried under high vacuum to yield the product as anoff-white solid (3.94 g, 96%). ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.84-1.96(m, 1H, gluCH); 2.00-2.10 (m, 1H, gluCH); 2.32 (s, 3H, CH₃, superimposedover t, 2H, gluCH₂); 2.71 (m, 2H, ArCH₂); 2.89 (m, 2H, ArCH₂); 4.28-4.36(m, 1H, gluCH); 7.20 (d, J=9 Hz, 2H, Ar); 7.39 (d, J=8 Hz, 1H, Ar); 7.62(dd, J=8, 2 Hz, 1H, Ar); 7.74 (d, J=9 Hz, 2H, Ar); 8.44 (d, J=8 Hz, 1H,gluNH); 9.21 (d, J=2 Hz, 1H, Ar); 10.73 (s, 1H, SO₂NH); 12.36 (br s, 2H,CO₂H); 12.72 (br s, 1H, NH). Anal Calculated for C₂₅H₂₄N₄O₈S.3/2H₂O: C,52.91; H, 4.79; N, 9.87; S, 5.65. Found: C, 52.98; H, 4.78; N, 9.87; S,5.58.

An essentially similar sequence of reactions using diethyl4-(methylamino)benzoylglutamate (T. R. Jones et al, UK PatentApplication GB 2175 903A, 1986) (2.0 g, 6.0 mmol) with the sulfonylchloride (2.0 g, 6.4 mmol) gave the corresponding product bearing amethyl substituent on the sulfonamido-nitrogen atom; data on the productand intermediate are given below.

DiethylN-(4-(methyl((1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonyl)amino)benzoyl)-L-glutamate

(1.47 g, 40%) M.P.=168-170.50° C. ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.14 (t,J=7 Hz, 3H, esterCH₃), 1.16 (t, J=7 Hz, 3H, esterCH₃), 1.85-2.20 (m, 2H,gluCH₂), 2.30 (s, 3H, C³—CH₃), 2.42 (t, J=7 Hz, 2H, gluCH₂), 2.67-2.80(m, 2H, ArCH₂), 2.85-2.99 (m, 2H, ArCH₂), 3.17 (s, 3H, NCH₃), 4.02 (q,J=7 Hz, 2H, esterCH₂), 4.08 (q, J=7 Hz, 2H, esterCH₂), 4.32-4.48 (m, 1H,gluCH), 7.22 (dd, J=8, 2 Hz, 1H, Ar), 7.28 (d, J=9 Hz, 2H, Ar), 7.38 (d,J=8 Hz, 1H, Ar), 7.82 (d, J=9 Hz, 2H, Ar), 8.73 (d, J=7 Hz, 1H, gluNH),9.00 (d, J=2 Hz, 1H, Ar), 12.68 (br s, 1H, N²H). Anal. Calculated forC₃₀H₃₄N₄O₈S.1/3H₂O: C, 58.44; H, 5.67; N, 9.09; S, 5.20. Found: C,58.46; H, 5.65; H, 9.09; S, 5.19.

N-(4-(Methyl((1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonyl)amino)benzoyl)-L-glutamicacid

(0.89 g, 99% from diester (1.0 g, 1.6 mmol); ¹H NMR (DMSO-d₆, 200 MHz)δ: 1.80-2.20 (m, 2H, gluCH₂), 2.31 (s, 3H, C³—CH₃), 2.34 (t, J=7 Hz, 2H,gluCH₂), 2.67-2.80 (m, 2H, ArCH₂), 2.85-2.98 (m, 2H, ArCH₂), 3.17 (s,3H, NCH₃), 4.30-4.43 (m, 1H, gluCH), 7.22 (dd, J=8, 2 Hz, 1H, Ar), 7.28(d, J=9 Hz, 2H, Ar), 7.38 (d, J=8 Hz, 1H, Ar), 7.83 (d, J=9 Hz, 2H, Ar),8.62 (d, J=8 Hz, 1H, gluNH), 9.00 (d, J=2 Hz, 1H, Ar), 12.39 (br s, 2H,CO₂H's), 12.69 (br s, 1H, N²H). Anal. Calculated forC₂₆H₂₆N₄O₈S.3/20H₂O: C, 56.04; H, 4.76; N, 10.05; S, 5.75. Found: C,56.04; H, 4.66; N, 10.03; S, 5.68.

EXAMPLE 291,2,5,6-Tetrahydro-3-methyl-4′-nitro-1-oxobenzo[f]quinazoline-9-sulfonanilide

1,2,5,6-Tetrahydro-3-methyl-1-oxobenzo[f]quinazolin-9-sulfonyl chloride(0.53 g, 1.7 mmole) and p-nitroaniline (0.25 g, 1.8 mmole) (Eastman)were dissolved in pyridine (5 ml) and the reaction mixture stirred atroom temperature for 48 hours. The pyridine was removed in vacuo, andthe residue washed with water. The dried solid was subjected tochromatography on silica (80 g), eluting with methanolmethylene chloride(1:19). Fractions containing product were evaporated to dryness, theresidue sonicated with ether (75 ml) and filtered. The beige solid waswashed with ether and dried under high vacuum to yield1,2,5,6-tetrahydro-3-methyl-4′-nitro-1-oxobenzo[f]quinazoline-9-sulfonanilide.(0.18 g, 26%). Mp>240° C. ¹H NMR (DMSO-d₆, 300 MHz) δ: 2.32 (s, 3H,CH₃); 2.72 (m, 2H, ArCH); 2.91 (m, 2H, ArCH₂); 7.33 (d, J=9 Hz, 2H, Ar);7.43 (d, J=8 Hz, 1H, Ar); 7.69 (dd, J=2,8 Hz, Ar); 8.13 (d, J=9 Hz, 2H,Ar); 9.23 (d, J=2 Hz, 1H, Ar); 11.13 (s, 1H, NH); 12.73 (s, 1H, NH).Anal Calculated for C₁₉H₁₆N₄O₅S.13/25H₂O: C, 54.10; H, 4.07; N, 13.28;S, 7.60. Found: C, 54.07; H, 3.98; N, 13.19; S, 7.66.

Similarly the following compounds were prepared by reaction of theappropriate aromatic amine with the foregoingbenzoquinazoline-9-sulfonyl chloride;

4′-Acetyl-1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]quinazoline-9-sulfonanilide

(0.172 g, 25%). Mp>240° C. ¹H NMR (DMSO-d₆, 300 MHz) δ: 2.32 (s, 3H,CH₃); 2.46 (s, 3H, CH₃); 2.71 (t, J=8 Hz, 2H, ArCH₂); 2.90 (t, J=8 Hz,2H, ArCH₂); 7.24 (d, J=9 Hz, 2H, Ar); 7.41 (d, J=8 Hz, 1H, Ar); 7.65(dd, J=8, 2 Hz, Ar); 7.83 (d, J=9 Hz, 2H, Ar); 9.21 (d, J=2 Hz, 1H, Ar);10.93 (s, 1H, NH); 12.73 (s, 1H, NH). Anal Calculated forC₂₁H₁₉N₃O₄S.8/25:EtOH3/20H₂O C, 60.88; H, 5.01; N, 9.84; S, 7.51. Found:C, 60.96; H, 4.85; N, 9.69; S, 7.45.

4′-Fluoro-1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]quinazoline-9-sulfonanilide

(0.07 g, 11%). Mp>260° C. ¹H NMR (DMSO-d₆, 200 MHz) δ: 2.30 (s, 3H,CH₃); 2.65-2.73 (m, 2H, ArCH₂); 2.83-2.92 (m, 2H, ArCH₂); 7.00-7.15 (m,4H, Ar); 7.34 (d, J=8 Hz, 1H, Ar); 7.49 (dd, J=2,8 Hz, 1H, Ar); 9.08 (d,J=2 Hz, 1H, Ar); 10.25 (s, 1H, NH); 12.68 (br s, 1H, NH). AnalCalculated for C₁₉H₆FN₃O₃S.H₂O C, 56.57; H, 4.50; N, 10.42; F, 4.71; S,7.95. Found: C, 56.17; H, 4.12; N, 10.26; F, 5.00; S, 8.13.

4-((1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzamide

(0.084 g, 6%). Mp=190° C. sintered. ¹H NMR (DMSO-d₆, 300 MHz) δ: 2.32(s, 3H, CH₃); 2.71 (t, J=8 Hz, ArCH₂); 2.89 (t, J=8 Hz, 2H, ArCH₂); 7.16(d, J=9 Hz, 2H, Ar); 7.22 (br s, 1H, NH); 7.39 (d, J=8 Hz, 1H, Ar); 7.62(dd, J=8, 2 Hz, 1H, Ar); 7.72 (d, J=8 Hz, 1H, Ar); 7.80 (br s, 1H, NH);9.19 (d, J=2H, 1H, Ar); 10.70 (s, 1H, NH); 12.72 (br s, 1H, NH). AnalCalculated for C₂₀H₁₈N₄O₄S.H₂O: C, 56.07; H, 4.70; N, 13.08; S, 7.48.Found: C, 56.11; H, 4.75; N, 12.99; S, 7.43.

EXAMPLE 30N-(4-((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamicacid

A. Diethyl N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamate

A solution of diethylN-(4-((1,2,5,6-tetrahydro-3-methyl-1-oxo-benzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamate(0.50 g, 0.84 mmol) in diglyme (10 ml) was stirred with 10% palladium oncarbon (0.25 g) (Aldrich) under nitrogen at reflux for 3 hours. Thesolution was diluted with diglyme (20 ml), filtered hot through celite,and concentrated under high vacuum. The resulting solid was suspended inhot methanol (50 ml), stirred overnight at room temperature, filtered,and dried under high vacuum to give diethylN-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamateas a white solid (0.25 g). ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.10 (t, J=7 Hz,3H, esterCH₃), 1.12 (t, J=7 Hz, 3H, esterCH₃), 1.78-2.15 (m, 2H,gluCH₂), 2.35 (t, J=7 Hz, 2H, gluCH₂), 2.4 3 (s, 3H, C³—CH₃), 3.98 (q,J=7 Hz, 2H, esterCH₂), 4.04 (q, J=7 Hz, 2H, esterCH₂), 2.35-4.39 (m, 1H,gluCH), 7.21 (d, J=9 Hz, 2H, Ar), 7.69 (d, J=9 Hz, 2H, Ar), 7.76 (d, J=9Hz, 1H, Ar), 7.91 (dd, J=9, 2 Hz, 1H, Ar), 8.19 (d, J=9 Hz, 1H, Ar),8.29 (d, J=9 Hz, 1H, Ar), 8.51 (d, J=7 Hz, 1H, gluNH), 10.44 (d, J=2 Hz,1H, Ar), 10.88 (br s, 1H, SO₂NH), 12.75 (br s, 1H, N H). Mass spectrum(CI-CH₄): 595 (M+1, 24.1%). Anal. Calculated for C₂₉H₃₀N₄O₈S: C, 58.58;H, 5.08; N, 9.42; S. 5.39. Found: C, 58.46; H, 5.10; N, 9.34; S. 5.41.

B.N-(4-((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamicacid

A solution of diethylN-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamate(0.22 g, 0.37 mmol) in ethanol (3 ml) and 0.25 N NaOH (12 ml) wasstirred at room temperature for 3 hours. The solution was slowlyacidified to pH 3 with 1N HCl and the resulting precipitate filtered,washed with water, and dried under high vacuum to giveN-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamicacid as a white solid (0.20 g). ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.73-2.15(m, 2H, gluCH₂), 2.27 (t, J=7 Hz, 2H, gluCH₂), 2.43 (s, 3H, CH₃),4.22-4.36 (m, 1H, gluCH), 7.20 (d, J=9 Hz, 2H, Ar), 7.69 (d, J=9 Hz, 2H,Ar), 7.76 (d, J=9 Hz, 1H, Ar), 7.90 (dd, J=9, 2 Hz, 1H, Ar), 8.18 (d,J=9 Hz, 1H, Ar), 8.28 (d, J=9 Hz, 1H, Ar), 8.39 (d, J=8 Hz, 1H, gluNH),10.44 (d, J=2 Hz, 1H, Ar), 10.86 (br s, 1H, SO₂NH), 12.32 (br s, 2H,CO₂H's), 12.75 (br s, 1H, N²H). Anal. Calculated forC₂₅H₂₂N₄O₈S.4/5H₂O): C, 54.30; H, 4.30; N, 10.13; S. 5.80. Found: C,54.29; H, 4.25; N, 10.13; S. 5.72.

EXAMPLE 31N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-7-yl)sulfonamido)benzoyl)-L-glutamicacid

A. DiethylN-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-7-yl)sulfonamido)benzoyl)-L-glutamate

Chlorosulfonic acid (15 ml) was reacted with3-methylbenzo[f]quinazolin-1(2H)-one (2.6 g, 12.4 mmoles) in the samemanner as described for the analogous 3-amino-5,6-dihydro compound(example 20) to obtain a mixture of1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-7-, 8-, and 9-sulfonylchlorides (2.91 g).

The foregoing mixture of sulfonyl chlorides was added to a solution ofN-(4-aminobenzoyl)-L-glutamic acid diethyl ester (3.85 g, 11.9 mmoles)in dry pyridine (30 ml) and stirred under a nitrogen atmosphere at roomtemperature for 19 hrs. After this time the solvent was evaporated underreduced pressure to leave a gummy residue which was suspended in water(100 ml) with vigorous stirring and sonication, filtered and dried. Thecrude mixture of products was subjected to six successive silica gelcolumn chromatography separations using methanol:methylene chloride(1:24 to 3:47) to obtain diethylN-(4-((1,2-dihydro-3-methyl-1-oxobenzo-[f]quinazolin-7-yl)sulfonamido)benzoyl)-L-glutamateas an off-white solid. (0.22 g, 3%) ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.10(t, J=7 Hz, 3H, ester-CH₃); 1.12 (t, J=7 Hz, 3H, ester-CH₃); 1.80-2.15(m, 2H, glu-CH₂); 2.35 (t, J=7.6 Hz, 2H, glu-CH₂); 2.43 (s, 3H,pyr-CH₃); 3.98 (q, J=7 Hz, 2H, ester-CH₂); 4.03 (q, J=7 Hz, 2H,ester-CH₂); 4.32 (m, 1H, glu-CH); 7.08 (d, J=8.6 Hz, 2H, Ar); 7.64 (d,J=8.4 Hz, 2H, Ar); 7.83 (t, J=8.2 Hz, 1H, Ar); 7.86 (d, J=8.6 Hz, 1H,Ar); 8.33 (d, J=7.5 Hz, 1H, glu-NH); 8.48 (d, J=7.3 Hz, 1H, Ar); 9.06(d, J=9.3 Hz, 1H, Ar); 10.18 (d, J=8.6 Hz, 1H, Ar); 11.15 (br s, 1H,NH); 12.73 (br s, 1H, NH). Anal. Calculated for C₂₉H₃₀N₄O₈S.1/4H₂O: C,58.14; H, 5.13; N, 9.35; S, 5.35. Found: C, 58.12; H, 5.16; N, 9.27; S,5.42.

B.N-(4-((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-7-yl)sulfonamido)benzoyl)-L-glutamicacid

A solution of diethylN-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-7-yl)sulfonamido)benzoyl)-L-glutamate(0.16 g, 0.3 mmoles) in 0.1 N NaOH (10 ml) was stirred at roomtemperature under a nitrogen atmosphere for 48 hrs, after which time thesolution was acidified (pH 3.5) with acetic acid. The precipitate wascollected, washed with water and dried to giveN-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-7-yl)sulfonamido)benzoyl)-L-glutamicacid as an off-white solid. (0.12 g, 86%) ¹H NMR (DMSO-d₆, 200 MHz) δ:1.72-2.08 (m, 2H, glu-CH₂); 2.26 (t, J=Hz, 2H, glu-CH₂); 2.43 (s, 3H,CH₃); 4.18-4.35 (m, 1H, glu-CH); 7.07 (d, J=8.4 Hz, 2H, Ar); 7.63 (d,J=8.3 Hz, 2H, Ar); 7.82 (t, J=7.3 Hz, 1H, Ar); 7.84 (d, J=8.9 Hz, 1H,Ar); 8.32 (m, 2H, glu-NH+Ar); 9.07 (d, J=9.3 Hz, 1H, Ar); 10.16 (d,J=8.8 Hz, 1H, Ar); 12.71 (br s, 1H, NH). Anal. Calculated forC₂₅H₂₂N₄O₈S.7/4H₂O: C, 52.67; H, 4.51; N, 9.83. Found: C, 52.52; H,4.36; N, 9.70.

EXAMPLE 32N-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)-L-glutamicacid

A. DiethylN-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)-L-glutamate

To a hot solution of 3,9-dimethylbenzo[f]quinazolin-1(2H)-one (2.0 g,8.9 mmol) in benzene (1000 ml) under nitrogen was addedN-bromosuccinimide (NBS) (2.0 g, 11 mmol). The solution was stirred atreflux for 1 hour and then concentrated in vacuo to give crude9-bromomethyl-3-methylbenzo[f]quinazolin-1(2H)-one. The solid wassuspended with diethyl N-(4-amino-2-fluorobenzoyl)-L-glutamate (T. R.Jones et al., UK Patent GB 2175 903A, 1986) (6.0 g, 18 mmol) in DMF (20ml) and stirred under nitrogen at 100° C. for 30 minutes. The reactionmixture was allowed to cool, N-methylmorpholine (1.0 ml, 9.1 mmol)(Aldrich) was added, and the solution concentrated under high vacuum.The residue was purified with silica gel chromatography eluting withmethylene chloride:THF (5:1). Fractions containing product wereconcentrated in vacuo to a thick paste, the solid suspended in a smallvolume of diethyl ether, filtered under nitrogen, and dried under highvacuum to give diethylN-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)-L-glutamateas a white solid (2.3 g). ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.15 (t, J=7 Hz,3H, esterCH₃), 1.18 (t, J=7 Hz, 3H, esterCH₃), 1.87-2.13 (m, 2H,gluCH₂), 2.38 (t, J=7 Hz, 2H, esterCH₂), 2.43 (s, 3H, C³—CH₃), 4.02 (q,J=7 Hz, 2H, esterCH₂), 4.09 (q, J=7 Hz, 2H, esterCH₂), 4.34-4.44 (m, 1H,gluCH), 4.57 (d, J=6 Hz, 2H, C⁹—CH₂), 6.39 (dd, J=15,2 Hz, 1H, Ar), 6.53(dd, J=9, 2 Hz, 1H, Ar), 7.30 (t, J=6 Hz, 1H, ArNH), 7.44 (dd, J=9, 9Hz, 1H, Ar), 7.60 (d, J=9 Hz, 1H, Ar), 7.61 (dd, J=8, 2Hz, 1H, Ar), 7.88(dd, J=7,5 Hz, 1H, gluNH), 8.01 (d, J=8 Hz, 1H, Ar), 8.22 (d, J=9 Hz,1H, Ar), 9.85 (s, 1H, Ar), 12.53 (s, 1H, N²H). Mass spectrum (CI-CH₄):563 (M+1, 100%). Anal. Calculated for C₃₀H₃₁FN₄O₆: C, 64.05; H, 5.55; N,9.96. Found: C, 64.14; H, 5.59; N, 9.94.

N-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)-L-glutamicacid

A solution of diethylN-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)-L-glutamate(2.3 g, 4.1 mmol) in ethanol (25 ml) and 0.2 N NaOH (100 ml) was stirredunder nitrogen at room temperature for 3 hours. The solution wasadjusted to pH 7 with 1N HCl and reduced in volume under vacuum toremove the ethanol. The product was precipitated by acidifying thesolution with 1N HCl to pH 3 with stirring under nitrogen. Thesuspension was stirred 15 minutes, filtered under nitrogen, washed withwater, pressed with a sheet of latex to remove excess water, and driedunder high vacuum to giveN-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzo-yl)-L-glutamicacid as a white solid (2.1 g). ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.82-2.12(m, 2H, gluCH₂), 2.29 (t, J=7 Hz, 2H, gluCH₂), 2.43 (s, 3H, C³—CH₃),4.32-4.42 (m, 1H, gluCH), 4.57 (d, J=6 Hz, 2H, C³—CH₂), 6.39 (dd, J=15,2Hz, 1H, Ar), 6.53 (dd, J=9, 2 Hz, 1H, Ar), 7.30 (t, J=6 Hz, 1H, ArNH),7.47 (dd, J=9, 9 Hz, 1H, Ar), 7.59 (d, J=9 Hz, 1H, Ar), 7.61 (dd, J=8, 2Hz, 1H, Ar), 7.73 (t, J=7 Hz, 1H, gluNH), 8.01 (d, J=8 Hz, 1H, Ar), 8.22(d, J=9 Hz, 1H, Ar), 9.85 (s, 1H, Ar), 12.42 (br s, 2H, CO₂H's), 12.53(s, 1H, N²H). Anal. Calculated for C₂₆H₂₃FN₄O₆.3/2H₂O.1/3NaCl: C, 56.49;H, 4.74; N, 10.14; Cl, 2.12; Na, 1.37. Found: C, 56.48; H, 4.64; N,10.20; Cl, 2.01; Na, 1.30.

An essentially similar sequence of reactions with diethyl4-aminobenzoyl-L-glutamate (2.8 g, 8.7 mmol) and diethyl4-methylamino(benzoyl)-L-glutamate (1.4 g, 4.2 mol) gave, upon couplingof each with 3,9-dimethylbenzo[f]quinazolin-1(2H)-one (0.5 g, 2.2 mmol)via the bromomethyl derivative;

i)N-(4(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glumaticacid, and

ii)N-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)-methyl)methylamino)benzoyl-L-glutamicacid:

data on these compounds and their diester intermediates are given below.

i) A. DiethylN-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamate

(0.57 g, 47%); ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H,esterCH₃), 1.17 (t, J=7 Hz, 3H, esterCH₃), 1.87-2.13 (m, 2H, gluCH₂),2.39 (t, J=7 Hz, 2H, gluCH₂), 2.43 (s, 3H, C³—CH₃), 4.03 (q, J=7 Hz, 2H,esterCH₂), 4.07 (q, J=7 Hz, 2H, esterCH₂), 4.31-4.41 (m, 1H, gluCH),4.57 (d, J=6 Hz, 2H, C³—CH₂), 6.64 (d, J=9 Hz, 2H, Ar), 7.02 (t, J=6 Hz,1H, ArNH), 7.57-7.67 (m, 4H, Ar), 8.00 (d, J=8 Hz, 1H, Ar), 8.21(overlapping d, J=8 Hz, 2H, Ar, gluNH), 9.85 (s, 1H, Ar), 12.53 (s, 1H,N²H). Mass spectrum (CI-CH₄): 545 (M+1, 94.8%), 342 (100%). Anal.Calculated for C₃₀H₃₂N₄O₆.1/10H₂O: C, 65.95; H, 5.94; N, 10.25. Found:C, 65.99; H, 5.94; N, 10.21.

i) B.N-(4(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glumaticacid

(0.48 g, 93% from diester (0.56 g, 1.02 mmol). ¹H NMR (DMSO-d₆, 300 MHz)δ: 1.82-2.12 (m, 2H, gluCH₂), 2.31 (t, J=7 Hz, 2H, gluCH₂), 2.43 (s, 3H,CH₃), 4.28-4.38 (m, 1H, gluCH), 4.57 (d, J=6 Hz, 2H, C⁹—CH₂), 6.64 (d,J=9 Hz, 2H, Ar), 7.00 (t, J=6 Hz, 1H, ArNH), 7.59 (d, J=9 Hz, 1H, Ar),7.63 (dd, J=8, 2 Hz, 1H, Ar), 7.63 (d, J=9 Hz, 2H, Ar), 8.00 (d, J=8 Hz,1H, Ar), 8.09 (d, J=8 Hz, 1H, gluNH), 8.21 (d, J=9 Hz, 1H, Ar), 9.85 (s,1H, Ar), 12.33 (br s, 2H, CO₂H's), 12.53 (s, 1H, N²H). Anal. Calculatedfor C₂₆H₂₄N₄O₆.H₂O: C, 61.65; H, 5.17; N, 11.06. Found: C, 61.51; H,5.01; N, 11.05.

ii) A. DiethylN(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)methylamino)benzoyl)-L-glutamate

(0.66 g, 53%. ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H,esterCH₃); 1.17 (t, J=7 Hz, 3H, esterCH₃), 1.88-2.13 (m, 2H, gluCH₂),2.40 (t, J=8 Hz, 2H, gluCH₂), 2.42 (s, 3H, C³—CH₃), 3.19 (s, 3H, NCH₃),4.03 (q, J=7 Hz, 2H, esterCH₂), 4.08 (q, J=7 Hz, 2H, esterCH₂),4.33-4.43 (m, 1H, gluCH), 4.91 (s, 2H, C⁹—CH₂), 6.81 (d, J=9 Hz, 2H,Ar), 7.44 (dd, J=8, 2 Hz, 1H, Ar), 7.58 (d, J=9 Hz, 1H, Ar), 7.72 (d,J=9 Hz, 2H, Ar), 7.98 (d, J=8 Hz, 1H, Ar), 8.20 (d, J=9 Hz, 1H, Ar),8.29 (d, J=7 Hz, 1H, gluNH), 9.76 (s, 1H, Ar), 12.48 (s, 1H, N²H). Massspectrum (CI-CH₄): 559 (M+1, 100%). Anal. Calculated for C₃₁H₃₄N₄O₆: C,66.65; H, 6.13; N, 10.03. Found: C, 66.46; H, 6.18; N, 9.98.

ii) B.N-(4-(((1,2-Di-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methylamino)benzoyl-L-glutamicacid

(0.58 g, 94% from diester (0.65 g, 1.2 mmol)). ¹H NMR (DMSO-d₆, 300 MHz)δ: 1.83-2.14 (m, 2H, gluCH₂), 2.32 (t, J=7 Hz, 2H, gluCH₂), 2.42 (s, 3H,C³—CH₃), 3.18 (s, 3H, NCH₃), 4.30-4.42 (m, 1H, gluCH), 4.91 (s, 2H,C⁹—CH₂), 6.81 (d, J=9 Hz, 2H, Ar), 7.44 (dd, J=8, 2 Hz, 1H, Ar), 7.58(d, J=9 Hz, 1H, Ar), 7.73 (d, J=9 Hz, 2H, Ar), 7.98 (d, J=8 Hz, 1H, Ar),8.18 (d, J=8 Hz, 1H, gluNH), 8.19 (d, J=9 Hz, 1H, Ar), 9.76 (s, 1H, Ar),12.32 (br s, 2H, CO₂H's), 12.50 (br s, 2H, N²H). Anal. Calculated forC₂₇H₂₆N₄O₆.7/5H₂O: C, 61.45; H, 5.50; N, 10.62. Found: C, 61.46; H,5.45; N, 10.59.

EXAMPLE 33(S)-2-(5-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)glutaricacid

A. Diethyl (S)-2-(4-nitrophthalimido)glutarate

Diisopropylethylamine (24 ml, 0.138 mole) (Aldrich) was added to asuspension of 4-nitrophthalic anhydride (25 g, 0.13 mole) (Tokyo Kasei)and L-glutamic acid diethyl ester hydrochloride (35 g, 0.146 mole)(Aldrich) in toluene (130 ml). The reaction mixture was stirred atreflux utilizing a Dean-Stark trap for 2.5 hours. After cooling, thesolution was diluted with diethyl ether (300 ml), washed with water (75ml), saturated NaHCO₃ solution (50 ml), dried (MgSO₄), and concentratedin vacuo at 70° C. to give diethyl (S)-2-(4-nitrophthalimido) glutarateas an oil that solidified to a white solid on standing (35.8 g).M.P.=65.5-66.5° C. ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.12 (t, J=7 Hz, 3H,esterCH₃), 1.14 (t, J=7 Hz, 3H, esterCH₃), 2.2-2.5 (m, 4H, gluCH₂CH₂),3.96 (q, J=7 Hz, 2H, esterCH₂), 4.08-4.19 (m, 2H, esterCH₂), 4.97-5.04(m, 1H, gluCH), 8.19 (dd, J=8,0.5 Hz, 1H, Ar), 8.56 (dd, J=2,0.5 Hz, 1H,Ar), 8.68 (dd, J=8, 2 Hz, 1H, Ar). Mass spectrum (CI-CH₄); 379 (M+1,28.8%), 333 (71.6%), 305 (100%). Anal. Calculated for C₁₇H₁₈N₂O₈: C,53.97; H, 4.80; N, 7.40. Found: C, 53.89; H, 4.82; N, 7.42.

B. Diethyl (S)-2-(4-aminophthalimido)glutarate

A suspension of diethyl (S)-2-(4-nitrophthalimido)glutarate (35.6 g,94.1 mmol) and 10% palladium on carbon (0.5 g) (Aldrich) in ethanol (200ml) was shaken under a hydrogen atmosphere (40-50 psi) for 26 hours. Thesolution was filtered through celite and concentrated in vacuo. Theresidue was purified by chromatography on silica gel (250 g) elutingwith diethyl ether:hexane (4:1) to give diethyl(S)-2-(4-aminophthalimido)glutarate as a viscous yellow oil (29.1 g). ¹HNMR (DMSO-d₆, 300 MHz) δ: 1.10 (t, J=7 Hz, 3H, esterCH₃), 1.12 (t, J=7Hz, 3H, esterCH₃), 2.17-2.39 (m, 4H, gluCH₂CH₂), 3.87-3.98 (m, 2H,esterCH₂), 4.05-4.18 (m, 2H, esterCH₂), 4.75-4.82 (m, 1H, gluCH), 6.57(br s, 2H, NH₂), 6.82 (dd, J=8, 2 Hz, 1H, Ar), 6.93 (d, J=2 Hz, 1H, Ar),7.51 (d, J=8 Hz, 1H, Ar). Mass spectrum (CI-CH₄) 349 (M+1, 40.8%), 303(60.1%), 275 (100%). Anal. Calculated for C₁₇H₂₀N₂O₆: C, 58.62; H, 5.79;N, 8.04. Found: C, 58.62; H, 5.80; N, 8.00.

C. Diethyl (S)-2-(5-amino-1-oxo-2-isoindolinyl)glutarate

A solution of diethyl (S)-2-(4-aminophthalimido)glutarate (10.5 g, 30.2mmol) in ethanol (150 ml) was cooled in an acetonitrile/CO₂ bath.Concentrated HCl (25 ml) was added followed by 30 mesh granular Zn (10.5g, 0.161 mole) (Fisher) when the internal temperature had reached −40°C. The reaction mixture was stirred 1.5 hours at this temperature and afurther 1 hour at −10° C. The excess of Zn was filtered from thesolution, 10% palladium on carbon (1.0 g) was added, and the solutionshaken under hydrogen at (30-50 psi) overnight. The catalyst was removedby filtration through celite and the filtrate concentrated in vacuo. Theresidue was made basic by the addition of saturated NaHCO₃ solution(^(˜)300 ml), extracted with diethyl ether (3×100 ml), and the etherextracts were dried (K₂CO₃) and concentrated in vacuo. The residue wasabsorbed onto silica gel (15 g) and purified by chromatography on silicagel (400 g) eluting with ethyl acetate:methylene chloride (1:4) to givediethyl (S)-2-(5-amino-1-oxo-2-isoindolinyl)glutarate as a viscous oil(4.14 g). ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.12 (t, J=7 Hz, 3H, 3H,esterCH₃), 1.17 (t, J=7 Hz, 3H, esterCH₃), 1.98-2.33 (m, 4H, gluCH₂CH₂),3.92-4.03 (m, 2H, esterCH₂), 4.11 (q, J=7 Hz, 2H, esterCH₂), 4.26 (verystrongly coupled AB pair, 2H, ArCH₂N), 4.77-4.84 (m, 1H, gluCH), 5.83(br s, 2H, NH₂), 6.58-6.65 (m, 2H, Ar), 7.32 (d, J=8 Hz, 1H, Ar). Massspectrum (CI-CH₄): 335 (M+1, 100%). Anal. Calculated for C₁₇H₂₂N₂O₅: C,61.07; H, 6.63; N, 8.38. Found: C, 60.93; H, 6.71; H, 8.30.

D. 9-Bromomethyl-3-methylbenzo[f]quinazolin-1(2H)-one

To a hot solution of 3,9-dimethylbenzo[f]quinazolin-1(2H)-one (4.00 g,17.9 mmol) in benzene (2000 ml) under nitrogen was addedN-bromo-succinimide (4.00 g, 22.5 mmol). The reaction mixture wasstirred just below reflux for 30 minutes, then at a gentle reflux for 30minutes. The resulting suspension was allowed to cool for 2 hours, thesolid filtered and dried at 70° C. under reduced pressure to give9-bromomethyl-3-methylbenzo[f]quinazolin-1(2H)-one (4.32 g, 83% purityby NMR). ¹H NMR (DMSO-d₆, 300 MHz) δ: 2.45 (s, 3H, CH₃), 4.96 (s, 2H,CH₂), 7.65 (d, J=9 Hz, 1H, Ar), 7.70 (dd, J=8, 2 Hz, 1H, Ar), 8.05 (d,J=8 Hz, 1H, Ar), 8.16 (d, J=9 Hz, 1H, Ar), 9.89 (s, 1H, Ar), 12.7 (br s,1H, NH).

E. Diethyl(S)-2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)glutarate

A solution of crude 9-bromomethyl-3-methylbenzo[f]quinazolin-1(2H)-one(4.32 g), (S)-diethyl 2-(5-amino-1-oxo-2-isoindolinyl) glutarate (4.0 g,12 mmol), and NaHCO₃ (2.0 g, 24 mmol) in DMF (30 ml) was stirred undernitrogen at 105° C. for 1.5 hours. After cooling, acetic acid (1 ml, 17mmol) was added, the reaction mixture transferred to a larger roundbottom flask with ethanol, and then concentrated in vacuo onto silicagel (30 g). The absorbed material was purified by chromatography onsilica gel eluting with methanol:methylene chloride (1:24) and thenprecipitation of the solid from methylene chloride (^(˜)20 ml) withethyl acetate (^(˜)45 ml) and methanol (^(˜)5 ml). The white solid wasfiltered under nitrogen and dried under high vacuum to give diethyl(S)-2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo[f]-quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)glutarate(3.27 g). ¹H NMR (DMSO-d₆, 300 MHz), δ: 1.10 (t, J=7 Hz, 3H, esterCH₃),1.15 (t, J=7 Hz, 3H, esterCH₃), 1.93-2.33 (m, 4H, gluCH₂CH₂), 2.43 (s,3H, C³—CH₃), 3.87-4.03 (m, 2H, esterCH₂), 4.09 (q, J=7 Hz, 2H,esterCH₂), 4.25 (very strongly coupled AB pair, 2H, gluNCH₂Ar), 4.58 (d,J=6 Hz, 2H, C⁹—CH₂N), 4.74-4.83 (m, 1H, gluCH), 6.71 (br d, J=2 Hz, 1H,Ar), 6.74 (dd, J=8, 2 Hz, 1H, Ar), 7.20 (t, J=6 Hz, 1H, ArNH), 7.37 (d,J=8 Hz, 1H Ar), 7.59 (d, J=9 Hz, 1H, Ar), 7.63 (dd, J=8, 2 Hz, 1H, Ar),8.00 (d, J=8 Hz, 1H, Ar), 8.21 (d, J=9 Hz, 1H, Ar), 9.87 (s, 1H, Ar),12.54 (s, 1H, N²H). Mass spectrum (CI-CH₄) 557 (M+1, 100%). Anal.Calculated for C₃₁H₃₂N₄O₆: C, 66.89; H, 5.79; N, 10.07. Found: C, 66.80;H, 5.82; N, 10.10.

F.(S)-2-(5-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)glutaricacid

A solution of diethyl(S)-2-(5-(((1,2-dihydro-3-methyl-1-oxo-benzo[f]quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)glutarate(3.20 g, 5.75 mmol) in 0.2 N NaOH (140 ml) was stirred under nitrogenfor 3 hours at room temperature. The solution was then slowly adjustedto pH 3 with 1 N HCl and the resulting suspension allowed to stirbriefly. The white solid was filtered under nitrogen, washed with water,and dried under high vacuum to give(S)-2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)glutaricacid (2.85 g). ¹H NMR (DMSO-d₆/D₂O, 300 MHz) δ: 1.86-2.34 (m, 4H,gluCH₂CH₂), 2.44 (s, 3H, CH₃), 4.25 (very strongly coupled AB pair, 2H,gluNCH₂Ar), 4.58 (s, 2H, C⁹—CH₂), 4.67-4.75 (m, 1H, gluCH), 6.69-6.77(m, 2H, Ar), 7.37 (d, J=8 Hz, 1H, Ar), 7.59 (d, J=9 Hz, 1H, Ar), 7.64(dd, J=8, 2 Hz, 1H, Ar), 8.01 (d, J=8 Hz, 1H, Ar), 8.22 (d, J=9 Hz, 1H,Ar), 9.85 (s, 1H, Ar). Anal. Calculated for C₂₇H₂₄N₄O₆.1.6H₂O: C, 61.27;H, 5.18; N, 10.58. Found: C, 61.29; H, 5.18; N, 10.57.

By a similar sequence of reactions, the N-methyl derivative of theforegoing compound was prepared by condensation of the bromomethylbenzoquinazoline with diethyl(S)-2-(5-(methylamino)-1-oxo-2-isoindolinyl)glutarate. The preparationof the latter, and physical data on the final benzoquinazoline productand diester intermediate are given below.

Diethyl (S)-2-(5-(methylamino)-1-oxo-2-isoindolinyl)glutarate

To a solution of diethyl (S)-2-(5-amino-1-oxo-2-isoindolinyl)glutarate(3.1 g, 9.3 mmol), 37% aqueous formaldehyde (0.81 g, 10 mmol), andacetic acid (0.5 ml) in ethanol (30 ml) was added sodiumcyanoborohydride (0.63 g, 10 mmol). After stirring the reaction mixturefor 45 minutes additional acetic acid (0.5 ml) and sodium borohydride(0.32 g, 5 mmol) were added and after a further 15 minutes additional37% aqueous formaldehyde (0.30 g, 3.7 mmol) was added. The reactionmixture was stirred for 1 hour, water (1 ml) was added, then the mixtureconcentrated in vacuo.

Purification by chromatography on silica gel eluting with ethylacetate:methylene chloride (1:6) gave diethyl(S)-2-(5-(methylamino)-1-oxo-2-isoindolinyl)glutarate (1.8 g). ¹H NMR(DMSO-d₆, 300 MHz) δ: 1.12 (t, J=7 Hz, 3H esterCH₃), 1.17 (t, J=7 Hz,3H, esterCH₃), 1.95-2.35 (m, 4H, gluCH₂'s), 2.74 (d, J=5 Hz, 3H, NCH₃),3.90-4.03 (m, 2H, esterCH₂), 4.11 (q, J=7 Hz, 2H, esterCH₂), 4.30 (verystrongly coupled AB pair, 2H, ArCH₂), 4.77-4.84 (m, 1H, gluCH), 6.43 (brq, J=5 Hz, 1H, NH), 6.58-6.64 (m, 2H, Ar), 7.38 (d, J=9 Hz, 1H, Ar).Anal. Calculated or C₁₈H₂₄N₂O₅3/10H₂O: C, 61.11; H, 7.01; N, 7.92.Found: C, 61.09; H, 7.03; N, 7.94.

Diethyl(S)-2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)methylamino)-1-oxo-2-isoindolinyl)glutarate

¹H NMR (DMSO-d₆, 300 MHz) δ: 1.10 (t, J=7 Hz, 3H, esterCH₃), 1.15 (t,J=7 Hz, 3H, esterCH₃), 1.97-2.35 (m, 4H, gluCH₂'s), 2.42 (s, 3H,C³—CH₃), 3.23 (s, 3H, NCH₃), 3.89-4.02 (m, 2H, esterCH₂), 4.10 (q, J=7Hz, 2H, esterCH₂), 4.30 (very strongly coupled AB pair, 2H, gluNCH₂Ar),4.77-4.84 (m, 1H, gluCH), 4.94 (s, 2H, C⁹—CH₂), 6.84-6.12 (m, 2H, Ar),7.45 (d, J=8.5 Hz, 2H, Ar), 7.58 (d, J=9 Hz, 1H, Ar), 7.99 (d, J=8.5 Hz,1H, Ar), 8.20 (d, J=9 Hz, 1H, Ar), 9.77 (s, 1H, Ar), 12.49 (s, 1H, N²H).Anal. Calculated for C₃₂H₃₄N₄O₆.1/4H₂O: C, 66.83; H, 6.05; N, 9.74.Found: C, 66.81; H, 5.97; N, 9.74.

(S)-2-(5-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)methylamino)-1-oxo-2-isoindolinyl)glutaricacid

¹H NMR (DMSO-d₆, 300 MHz) δ: 1.88-2.35 (m, 4H, gluCH₂'s), 2.43 (s, 3H,C³—CH₃), 3.22 (s, 3H, NCH₃), 4.31 (s, 2H, gluNCH₂Ar), 4.67-4.76 (m, 1H,gluCH), 4.93 (s, 2H, C⁹—CH₂), 6.87 (dd, J=8.5, 2 Hz, 1H, Ar), 6.91 (s,1H, Ar), 7.44 (d, J=8.5 Hz, 1H, Ar), 7.46 (dd, J=8.5, 1.5 Hz, 1H, Ar),7.58 (d, J=9 Hz, 1H, Ar), 7.99 (d, J=8.5 Hz, 1H, Ar), 8.20 (d, J=9 Hz,1H, Ar), 9.76 (s, 1H, Ar), 11.8-13.0 (br s, 2H, CO₂H's), 12.52 (br s,1H, N²H). Anal. Calculated for C₂₈H₂₆N₄O₆.2H₂O: C, 61.08; H, 5.49; N,10.18. Found: C, 61.14; H, 5.22; N, 10.18.

EXAMPLE 34(S)-2-(2.3-Dihydro-6-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-3-oxo-1,2-benxisothiazol-2-yl)glutaricacid

A. 2,2′-Dithiobis(4-nitrobenzoic acid) (Adapted from Organic SynthesesColl. Vol. 2, p. 580).

A suspension of 4-nitroanthranilic acid (32.7 g, 180 mmol) (Aldrich) inwater (100 ml) and concentrated HCl (35 ml) was stirred 30 minutes atroom temperature and then chilled in an ice bath. A solution of sodiumnitrite (12.4 g, 180 mmol) in water (25 ml) was added in small aliquotsbelow the surface of the suspension via pipette. Crushed ice was addedduring the addition to maintain an internal temperature below 50° C. Thereaction mixture was then stirred 1 hour at 0° C.

In a 1 liter flask, sulphur (6.4 g, 0.20 mole) and Na₂S.9H₂O (48 g, 0.20mole) were dissolved in hot water (100 ml). A solution of NaOH (7.2 g,0.18 mole) in water (40 ml) was added and the resulting solution cooledin an ice bath. The solution of diazonium salt was then added inaliquots (15-25 ml) along with crushed ice to maintain an internaltemperature below 5° C. The reaction mixture was stirred 2 hours at roomtemperature, filtered, and the filtrate adjusted to neutral pH withacetic acid. The solution was treated with activated charcoal (5 g),filtered, adjusted to pH 2.5-3.0 with concentrated HCl and the resultingprecipitate was filtered and washed with water. The solid was nearlydissolved in hot ethanol (200 ml), treated with activated charcoal (5g), filtered, concentrated in vacua, then resuspended in methanol(^(˜)80 ml), filtered and dried under reduced pressure at 110° C. togive crude 2,2′-dithiobis(4-nitrobenzoic acid) (9.9 g). An analyticalsample was prepared by recrystallization from methanol and was driedunder reduced pressure at 120° C. ¹H NMR (DMSO-d₆, 300 MHz) δ: 8.15 (dd,J=9, 2 Hz 1H, Ar), 8.27 (d, J=9 Hz, 1H, Ar), 8.39 (d, J=2 Hz, 1H, Ar).Anal. Calculated for C₁₄H₈N₂O₈S₂: C, 42.43; H, 2.03; N, 7.07; S, 16.18.Found: C, 42.48; H, 2.04; N, 7.12; S, 16.25.

B. Diethyl(S)-2-(2,3-dihydro-6-nitro-3-oxo-1,2-benzisothiazol-2-yl)glutarate

A solution of crude 2,2′-dithiobis (4-nitrobenzoic acid) (8.35 g, ^(˜)21mmol) in SOCl₂ (50 ml) was stirred at reflux for 1.5 hours and thenconcentrated in vacuo. The residual solid was suspended in methylenechloride (50 ml) and Cl₂ (3.3 g, 47 mmol) gas was bubbled in and thesolution stirred 1.5 hours at room temperature. Nitrogen gas was thenbubbled into the solution until moistened starch-iodine paper indicatedthe absence of Cl₂. L-Glutamic acid diethyl ester hydrochloride (6.5 g,27 mmol) (Aldrich) was then added, followed by the dropwise addition ofdiisopropylethylamine (^(˜)10 ml, ^(˜)57 mmol) (Aldrich) and thereaction mixture was stirred under nitrogen for 45 minutes. Additionaldiisopropylethylamine was added dropwise until formation of white aminehydrochloride fumes above the solution ceased. After a further 30minutes of stirring, the reaction mixture was concentrated in vacuo ontosilica gel (40 g); chromatography on silica gel (200 g), eluting withethyl acetate:hexane (1:2) gave diethyl(S)-2-(2,3-dihydro-6-nitro-3-oxo-1,2-benzoisothiazol-2-yl)glutarate (4.0g) as an oil. ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.14 (t, J=7 Hz, 3H,esterCH₃), 1.18 (t, J=7 Hz, 3H, esterCH₃), 2.12-2.46 (m, 4H, gluCH₂CH₂),4.01 (q, J=7 Hz, 2H, esterCH₂), 4.17 (q, J=7 Hz, 2H, esterCH₂),5.22-5.29 (m, 1H, gluCH), 8.11 (d, J=9 Hz, 1H, Ar), 8.21 (dd, J=9, 2 Hz,1H, Ar), 9.03 (d, J=2 Hz, 1H, Ar). Anal. Calculated for C₁₆H₈N₂O₇S: C,50.26; H, 4.74; N, 7.33; S, 8.38. Found: C, 50.35; H, 4.76; N, 7.33; S,8.28.

C. Diethyl(S)-2-(6-amino-2.3-dihydro-3-oxo-1,2-benzisothiazol-2-yl)glutarate

A solution of diethyl(S)-2-(2,3-dihydro-6-nitro-3-oxo-1,2-benzisothiazol-2-yl)glutarate (4.0g, 10 mmol) and suspended iron (1.0 g, 18 mmol) in acetic acid (100 ml)was stirred under nitrogen for 1 hour at 550° C. Additional iron (3×0.25g, 13 mmol) was added at intervals of 1, 1.25, and 1.75 hours. Thereaction mixture was stirred 30 minutes after the last addition,filtered, concentrated in vacuo, and the residue absorbed onto silicagel (20 g) from a methylene chloride solution. Purification bychromatography on silica gel (150 g) eluting with ethyl acetate:hexane(1:1→2:1) gave diethyl(S)-2-(6-amino-2,3-dihydro-3-oxo-1,2-benzisothiazol-2-yl)glutarate (3.3g) as an oil. ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H,esterCH₃), 1.17 (t, J=7 Hz, 3H, esterCH₃), 1.95-2.38 (m, 4H, gluCH₂CH₂),4.02 (q, J=7 Hz, 2H, esterCH₂), 4.13 (q, J=7 Hz, 2H, esterCH₂),5.08-5.15 (m, 1H, gluCH), 6.09 (br s, 2H, NH₂), 6.62 (dd, J=9, 2 Hz, 1H,Ar), 6.84 (d, J=2 Hz, 1H, Ar), 7.50 (d, J=9 Hz, 1H, Ar). Mass spectrum(CI-CH₄): 353 (M+1, 100%). Anal. Calculated for C₁₆H₂₀N₂O₅S: C, 54.53;H, 5.72; N, 7.95; S, 9.10. Found: C, 54.34; H, 5.73; N, 7.87; S, 9.00.

D. Diethyl(S)-2-(2,3-Dihydro-6-(((1,2-dihydro-3-methyl-1-oxo-benzo[f]quinazolin-9-yl)methyl)amino)-3-oxo-1,2-benzisothiazol-2-yl)glutarate

(0.34 g) was prepared by condensation of the foregoing ester (3.2 g, 9.1mmol) with 9-bromomethyl-3-methylbenzo[f]quinazolin-1(2H)-one (2.3 g)essentially as described in the previous example. ¹H NMR (DMSO-d₆, 300MHz) δ: 1.12 (t, J=7 Hz, 3H, esterCH₃), 1.14 (t, J=7 Hz, 3H, esterCH₃),1.93-2.34 (m, 4H, gluCH₂CH₂), 2.42 (s, 3H, C³—CH₃), 4.00 (q, J=7 Hz, 2H,esterCH₂), 4.11 (q, J=7 Hz, 2H, esterCH₂), 4.59 (d, J=6 Hz, 2H, C⁹—CH₂),5.06-5.14 (m, 1H, gluCH), 6.79 (dd, J=9, 2 Hz, 1H, Ar), 6.92 (d, J=2 Hz,1H, Ar), 7.44 (t, J=6 Hz, 1H, ArNH), 7.53 (d, J=9 Hz, 1H, Ar), 7.59 (d,J=9 Hz, 1N, Ar), 7.63 (dd, J=8, 2 Hz, 1H, Ar), 8.01 (d, J=8 Hz, 1H, Ar),8.21 (d, J=9 Hz, 1H, Ar), 9.86 (s, 1H, Ar), 2.54 (s, 1H, N²H). Massspectrum (CI-CH₄) 575 (M+1, 36.5%). Anal. Calculated for C₃₀H₃₀N₄O₆S: C,62.70; H, 5.26; N, 9.75; S, 5.58. Found: C, 62.62; H, 5.28; H, 9.73; S,5.48.

E.(S)-2-(2.3-Dihydro-6-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-3-oxo-1,2-benzisothiazol-2-yl)glutaricacid was obtained by hydrolysis of the foregoing diester essentially asdescribed in the previous example.

¹H NMR (DMSO-d₆, 300 MHz) δ: 1.88-2.38 (m, 4H, gluCH₂CH₂), 2.43 (s, 3H,CH₃), 4.60 (br d, J=5 Hz, 2H, C⁹—CH₂), 4.98-5.08 (m, 1H, gluCH), 6.78(dd, J=9, 2 Hz, 1H, Ar), 6.92 (d, J=2 Hz, 1H, Ar), 7.41 (br t, J=6 Hz,1H, ArNH), 7.53 (d, J=9 Hz, 1H, Ar), 7.59 (d, J=9 Hz, 1H, Ar), 7.63 (dd,J=8, 2 Hz, 1H, Ar), 8.02 (d, J=8 Hz, 1H, Ar), 8.22 (d, J=9 Hz, 1H, Ar),9.86 (s, 1H, Ar), 11.8-13.3 (3H, CO₂H's and N²H). Anal. Calculated forC₂₆H₂₂N₄O₆S.2H₂O: C, 56-31; H, 4.73; N, 10.10. Found: C, 56.28; H, 4.65;N, 10.13.

Analogs ofN-(4(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)-methyl)amino)benzoyl)-L-glutamicacid (Example 32) were often prepared by coupling of an appropriatelyprotected p-aminobenzoylglutamate analog with9-bromomethyl-3-methylbenzo[f]quinazolin-1(2H)-one followed byhydrolysis of the glutamate diesters.

The analog of the above compounds where the benzene ring of thep-aminobenzoic acid moiety had been replaced by a thiophene ring wasprepared by condensation of diethyl 5-amino-2-thenoyl-L-glutamate (L. R.Hughes, U.K. Patent GB 2188319A) with the requisite9-bromomethylbenzoquinazoline essentially as described above.

DiethylN-((5-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-thienyl)carbonyl)-L-glutamate

¹H NMR (DMSO-d₆, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H, esterCH₃), 1.17 (t,J=7 Hz, 3H esterCH₃), 1.82-2.10 (m, 2H, gluCH₂), 2.38 (t, J=7.5 Hz, 2H,gluCH₂), 2.43 (s, 3H, C³—CH₃), 4.03 (q, J=7 Hz, 2H, esterCH₂), 4.08 (q,J=7 Hz, 2H, esterCH₂), 4.26-4.36 (m, 1H, gluCH), 4.51 (d, J=5.5 Hz, 2H,C⁹—CH₂), 5.90 (d, J=4 Hz, 1H, Ar), 7.46 (d, J=4 Hz, 1H, Ar), 7.60 (d,J=9 Hz, 1H, Ar), 7.63 (dd, J=8, 1.5 Hz, 1H, Ar), 7.70 (t, J=5.5 Hz, 1H,ArNH), 8.01 (d, J=8.5 Hz, 1H, Ar), 8.14 (d, J=7.5 Hz, 1H, gluNH), 8.22(d, J=9 Hz, 1H, Ar), 9.84 (s, 1H, Ar), 2.55 (s, 1H, N²H). Mass spectrum(CI-CH₄): 551 (M+1, 90.3%), 329 (100%). Anal. Calculated forC₂₈H₃₀N₄O₆S.4/3H₂O; C, 58.53; H, 5.73; N, 9.75; S, 5.58. Found C, 58.48;H, 5.61; N, 9.71; S, 5.65.

N-((5-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino-2-thienyl)carbonyl)-L-glutamicacid

¹H NMR (DMSO-d₆, 300 MHz) δ: 1.77-2.08 (m, 2H, gluCH₂), 2.30 (t, J=5 Hz,gluCH₂), 2.43 (s, 3H, CH₃), 4.22-4.32 (m, 1H, gluCH), 4.51 (d, J=5.5 Hz,2H, C⁹—CH₂), 5.89 (d, J=4 Hz, 1H, Ar), 7.46 (d, J=4 Hz, 1H, Ar),7.58-7.70 (m, 3H, 2 Ar & ArNH), 8.01 (d, J=8 Hz, 1H, Ar), 8.03 (d, J=7.5Hz, 1H, gluNH), 8.22 (d, J=9 Hz, 1H, Ar), 9.84 (s, 1H, Ar), 12.34 (br s,2H, CO₂H's), 12.55 (s, 1H, N²H). Anal. Calculated forC₂₄H₂₂N₄O₆S.4/3H₂O: C, 55.60; H, 4.79; N, 10.81; S, 6.18. Found: C,55.60; H, 4.69; N, 10.73; S, 6.16.

An analog in which the NH of the glutamate moiety was replaced by amethylene group was also prepared by a similar sequence of reactions.The preparation of the requisite side chain moiety and analytical dataon the final products are given below.

(RS)-2-(2-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)phenyl)-2-oxoethyl)glutaricacid

A. Diethyl 2-ethoxycarbonyl-2-(2-(4-nitrophenyl)-2-oxoethyl)glutarate

To a solution of diethyl 2-ethoxycarbonyl glutarate (11 g, 42 mmol) indiethyl ether:dimethylformamide (1:1, 90 ml) at 0° C. was added NaOMe(2.16 g, 40 mmol). After stirring the mixture for 15 minutes a solutionof 2-tiromo-4′-nitoacetophenone in diethyl ether:dimethylformamide (1:1,30 ml) was added dropwise over 5 minutes. The reaction mixture wasremoved from the ice bath, stirred for 30 minutes, diluted with water(200 ml) and extracted with diethyl ether (2×75 ml). The organicsolution was washed with 10% LiCl solution (40 ml), dried (MgSO₄), andconcentrated in vacuo. Purification by repeated chromatography on silicagel eluting with ethylacetate:hexane (1:4) and ethylacetate:methylenechloride:hexane (1:1:8) gave diethyl2-ethoxycarbonyl-2-(2-(4-nitrophenyl)-2-oxoethyl)glutarate (2.8 g) as anoil ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.12 (t, J=7 Hz, 6H, CH₃, s), 1.13 (t,J=7 Hz, 3H, CH₃), 2.18-2.42 (m, 4H, CH₂CH₂), 3.75 (s, 2H, COCH₂), 3.99(q, J=7 Hz, 2H, esterCH₂), 4.11 (q, J=7 Hz, 4H, esterCH₂'s), 8.20 (d,J=9 Hz, 2H, Ar), 8.33 (d, J=9 Hz, 2H, Ar). Anal. Calculated forC₂₀H₂₅NO₉: C, 56.73; H, 5.95; N, 31. Found: C, 56.66; H, 5.83; N, 3.36.

B. Diethyl (RS)-2-(2-(4-nitrophenyl)-2-oxoethyl)glutarate

A solution of diethyl2-ethoxycarbonyl-2-(2-(4-nitrophenyl)-2-oxoethyl)glutarate (2.5 g, 5.9mmol) in ethanol:1N NaOH (2:1, 105 ml) was stirred 20 hours at roomtemperature and then acidified to pH 1.5 with concentrated HCl andconcentrated in vacuo. The residue was dissolved in diglyme (50 ml) andthe solution stirred at reflux for 20 minutes and then concentrated invacuo. The residue was then dissolved in ethanol (50 ml). HCl gas wasbubbled into the solution for 30 seconds, and the solution was stirredat room temperature over the weekend and then concentrated in vacuo. Theproduct was taken up in diethyl ether (100 ml), washed with saturatedsodium bicarbonate solution (35 ml), dried (MgSO₄), and concentrated invacuo. Purification by chromatography on silica gel eluting with ethylacetate:hexane (1:4) gave diethyl(RS)-2-(2-(4-nitrophenyl)-2-oxoethyl)glutarate (1.49 g) as an oil ¹H NMR(DMSO-d₆, 200 MHz) δ: 1.13 (t, J=7 Hz, 3H, CH₃), 1.19 (t, J=7 Hz, 3H,CH₃), 1.74-1.93 (m, 2H, CH₂), 2.35-2.45 (m, 2H, CH₂CO₂), 2.82-3.00 (m,1H, CH), 3.24-3.67 (m, 2H, COCH₂), 4.03 (q, J=7 Hz, 2H, esterCH₂), 4.04(q, J=7 Hz, 2H, esterCH₂), 8.20 (d, J=9 Hz, 2H, Ar), 8.33 (d, J=9 Hz,2H, Ar). Anal. Calculated for C₁₇H₂₁NO₇.1/4H₂O: C, 57.38; H, 6.09; N,3.94. Found: C, 57.35; H, 6.11; N, 3.89.

C. Diethyl (RS)-2-(2-(4-aminophenyl)-2-oxoethyl)glutarate

A solution of diethyl (RS)-2-(2-(4-nitrophenyl)-2-oxoethyl)glutarate(1.48 g, 4.2 mmol) and 10% palladium on carbon (0.23 g) in ethanol (100ml) was shaken under hydrogen (30-35 psi)for 40 minutes. The catalystwas filtered off and the filtrate concentrated in vacuo. Purification bychromatography on silica gel eluting with ethyl acetate:hexane (1:1)gave diethyl (RS)2-(2-(4-aminophenyl)-2-oxoethyl)glutarate (1.07 g) asan oil that solidified on standing. M.P. 58-61° C. ¹H NMR (DMSO-d₆), 200MHz) δ: 1.13 (t, J=7 Hz, 3H, CH₃), 1.16 (t, J=7 Hz, 3H, CH₃), 1.67-1.87(m, 2H, CH₂), 2.28-2.40 (m, 2H, CH₂CO₂), 2.72-2.88 (m, 1H, CH), 2.99(ABX, apparent J_(AB)=17.5 Hz, J_(AX)=4.5 Hz, 1H, COCH—H), 3.19 (ABX,apparent J_(AB)=17.5 Hz, J_(BX)=9.5 Hz, 1H, COCH—H), 4.00 (q, J=7 Hz,2H, esterCH₂), 4.03 (q, J=7 Hz, 2H, esterCH₂), 6.04 (br s, 2H, NH₂),6.53 (d, J=9 Hz, 2H, Ar), 7.66 (d, J=9 Hz, 2H Ar). Mass spectrum(CI-CH₄): 322 (M+1, 94.4%), 276 (100%). Anal. Calculated forC₁₇H₂₃NO₅.0.15H₂O: C, 63.01; H, 7.25; N, 4.32. Found: C, 62.98; H, 7.24;N, 4.28.

D. Diethyl(RS)-2-(2-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)phenyl)-2-oxoethyl)glutarate

M.P.=189-190° C. ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.13 (t, J=7 Hz, 3H,esterCH₃), 1.17 (t, J=7 Hz, 3H, esterCH), 1.67-1.88 (m, 2H, CH₂),2.30-2.40 (m, 2H, CH₂CO₂), 2.43 (s, 3H, C³—CH₃), 2.73-2.89 (m, 1H, CH),3.00 (ABX, apparent J_(AB)=17.5 Hz, J_(AX)=4.5 Hz, 1H, COCH—H), 3.22(ABX, apparent J_(AB)=17.5 Hz, ABX=9.5 Hz, 1H, COCH—H), 4.01 (q, J=7 Hz,2H, esterCH₂), 4.04 (q, J=7 Hz, 2H, esterCH₂), 4.60 (br d, J=5.5 Hz, 2H,C⁹—CH₂), 6.66 (d, J=9 Hz, 2H, Ar), 7.39 (br, t, J=5.5 Hz, 1H, ArNH),7.60 (d, J=9 Hz, 1H, Ar), 7.62 (dd, J=8, 1.5 Hz, 1H, Ar), 7.71 (d, J=Hz,2H, Ar), 8.01 (d, J=8.5 Hz, 1H, Ar), 8.22 (d, J=9 Hz, 1H, Ar), 9.85 (s,1H, Ar), 12.53 (s, 1H, N²—H). Mass spectrum (CI-CH₄): 544 (M+1, 100%).Anal. Calculated for C₃₁H₃₃N₃O₆: C, 68.49; H, 6.12; N, 7.73. Found: C,68.43; H, 6.15; N, 7.72.

E.(RS)-2-(2-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)phenyl)-2-oxoethyl)glutaricacid

¹H NMR (DMSO-d₆/D₂O, 300 MHz, δ: 1.63-1.85 (m, 2H, CH₂), 2.17-2.37 (m,2H, CH₂CO₂), 2.43 (s, 3H, C³—CH₃), 2.70-2.82 (m, 1H, CH), 2.91 (ABX,apparent J_(AB)=17.5 Hz, J_(AX)=4 Hz, 1H, COCH—H), 3.17 (ABX, apparentJ_(AB)=17.5 Hz, J_(BX)=9.5 Hz, 1H, COCH—H), 4.59 (s, 2H, C⁹—CH₂), 6.65(d, J=9 Hz, 2H, Ar), 7.59 (d, J=9 Hz, 1H, Ar), 7.61 (dd, J=8.5, 1.5 Hz,1H, Ar), 7.70 (d, J=9 Hz, 2H, Ar), 8.00 (d, J=8.5 Hz, 1H, Ar), 8.21 (d,J=9H, 1H, Ar), 9.83 (s, 1H, Ar). Anal. Calculated for C₂₇H₂₅N₃O₆.7/4H₂O: C, 62.48; H, 5.53; N, 8.10. Found: C, 62.46; H, 91.42; N, 8.06.

Analogs in which the aminomethylene moiety of the bridge was replaced bytwo-carbon moieties were also prepared;

(E)-N-(4-(2-(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)vinyl)benzoyl-L-glutamicacid

A. Diethyl(E)-N-(4-(2-(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)vinyl)benzoyl-L-glutamate

A solution of 9-bromo-3-methylbenzo[f]quinazolin-1(2H)-one (0.87 g, 3.0mmol), 4-vinylbenzoic acid (0.87 g, 5.9 mmol), palladium acetate (0.45g, 2.0 mmol), and tri(2-tolyl)phosphine (1.2 g, 3.9 mmol) inN-methylmorpholine (90 ml) was stirred under nitrogen at reflux for 1hour. Additional palladium acetate (0.45 g, 2.0 mmol) andtri(2-tolyl)phosphine (1.2 g, 3.9 mmol) were added and the reactionmixture was refluxed for a further 4 hours. The resulting suspension wasallowed to cool, the solid filtered and washed with diethyl ether. Thesolid was resuspended in a small volume of boiling ethanol, filteredhot, washed with diethyl ether and dried under vacuum at 80° C. to give4-(2-(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)vinyl)benzoicacid ¹H NMR (DMSO-d₆, 300 MHz) δ: 2.44 (s, 3H, CH₃), 7.50 (d, J=16.5 Hz,1H, vinylCH), 7.61 (d, J=8 Hz, 1H, Ar), 7.65 (d, J=16 Hz, 1H, vinylCH),7.83 (d, J=8 Hz, 2H, Ar), 7.96 (d, J=8 Hz, 2H, Ar), 8.05 (s, 2H, Ar),8.23 (d, J=9 Hz, 1H, Ar), 9.96 (s, 1H, Ar), 12-13.2 (v br s, 1H, CO₂H),12.6 (br s, 1H, N²H) containing 6.7% by NMR of9-bromo-3-methylbenzo[f]quinazolin-1-(2H)-one (0.80 g). To a suspensionof the acid in a solution of L-glutamic acid diethyl ester hydrochloride(0.72 g, 3.0 mmol) and triethylamine (0.42 ml, 3.0 mmol) indimethylformamide (50 ml) was added1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (0.48 g, 2.5mmol). After stirring the mixture for 4 hours, more dimethylformamide(50 ml) was added and the suspension stirred overnight. The reactionmixture was heated to 65° C.,1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (0.32 g, 1.7mmol) was added and the suspension was stirred for 6 hours to give ahomogeneous solution. The solution was stirred for 60 hours at roomtemperature, then concentrated in vacuo onto silica gel (log).Purification by chromatography on silica gel (450 g) eluting withmethanol:methylene chloride (1:39 to 1:24), evaporation, filtration ofthe resulting solid from a small volume of methanol and drying underhigh vacuum gavediethyl(E)-N-(4-(2-(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)vinyl)benzoyl)-L-glutamate(0.22 g). ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.17 (t, J=7 Hz, 3H, esterCH₃),1.20 (t, J=7 Hz, 3H, esterCH₃), 1.95-2.20 (m, 2H, gluCH₂), 2.44 (s, 3H,C³—CH₃), 2.47 (t, J=7 Hz, 2H, gluCH₂), 4.06 (q, J=7 Hz, 2H, esterCH₂),4.12 (q, J=7 Hz, 2H, esterCH₂), 4.41-4.51 (m, 1H, gluCH), 7.50 (d,J=16.5 Hz, 1H, vinylCH), 7.61 (d, J=9 Hz, 1H, Ar), 7.64 (d, J=16.5 Hz,1H, vinylCH), 7.83 (d, J=8.5 Hz, 2H, Ar), 7.93 (d, J=8.5 Hz, 2H, Ar),8.05 (s, 2H, Ar), 8.24 (d, J=9 Hz, 1H, Ar), 8.76 (d, J=7.5 Hz, 1H,gluNH), 9.96 (s, 1H, Ar), 12.58 (br, s, 1H, N²H). Mass spectrum(CI-CH₄): 542 (M+1, 100%). Anal. Calculated for C₃₁H₃N₃O₆.0.55H₂O: C,67.51; H, 5.87; N, 7.62. Found: C, 67.40; H, 5.72; N, 7.67.

B.(E)-N-(4-(2-(1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)vinyl)benzoyl)-L-glutamicacid was obtained by base hydrolysis of the foregoing glutamate diesterby the method described above.

¹H NMR (DMSO-d₆, 300 MHz) δ: 1.91-2.20 (m, 2H, gluCH₂), 2.39 (t, J=7.5Hz, 2H, gluCH₂), 2.45 (s, 3H, C³—CH₃), 4.38-4.48 (m, 1H, gluCH), 7.51(d, J=16.5 Hz, 1H, vinylCH), 7.62 (d, J=8.5 Hz, 1H, Ar), 7.65 (d, J=16.5Hz, 1H, vinylCH), 7.84 (d, J=8.5 Hz, 2H, Ar), 7.94 (d, J=8.5 Hz, 2H,Ar), 8.06 (s, 2H, Ar), 8.25 (d, J=9 Hz, 1H, Ar), 8.66 (d, J=6 Hz, 1H,gluNH), 9.96 (s, 1H, Ar), 12.0-12.8 (br s, 2H, CO₂H's), 12.61 (br s,N²H). Anal. Calculated for C₂₇H₂₃N₃O₆.H₂O: C, 64.41; H, 5.00; N, 8.35.Found: C, 64.60; H, 4.90; N, 8.29.

N-(4-(2-(1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)ethyl)benzoyl)-L-glutamicacid

A. DiethylN-(4-(2-(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)ethyl)benzoyl)-L-glutamate

A suspension of diethylN-(4-(2-(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)vinyl)benzoyl)-L-glutamate(0.16 g, 0.29 mmol) and 10% palladium on carbon (0.10 g) in ethanol (100ml) was shaken under hydrogen (40 psi) overnight. Ethanol (80 ml) andacetic acid (20 ml) were added and the mixture was hydrogenated (40 psi)for 1 day. The solution was filtered, concentrated in vacuo, and theresidue and catalyst were recombined in acetic acid (40 ml) andhydrogenated over the weekend. The solution was filtered, concentratedin vacuo and the product twice filtered from a small volume of methanolto give diethylN-(4-(2-(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)ethyl)benzoyl)-L-glutamate(0.10 g). ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.16 (t, J=7 Hz, 3H, esterCH₃),1.19 (t, J=7 Hz, 3H, esterCH₃), 1.90-2.18 (m, 2H, gluCH₂), 2.43 (s, 3H,C³—CH₃), 2.44 (t, J=7.5 Hz, 2H, gluCH₂), 3.03-3.22 (m, 4H, ArCH₂'s),4.04 (q, J=7 Hz, 2H, esterCH₂), 4.10 (q, J=7 Hz, 2H, esterCH₂),4.37-4.47 (m, 1H, gluCH), 7.40 (d, J=8 Hz, 2H, Ar), 7.54 (dd, J=8, 1.5Hz, 1H, Ar), 7.57 (d, J=8.5 Hz, 1H, Ar), 7.80 (d, J=8 Hz, 2H, Ar), 7.95(d, J=8 Hz, 1H, Ar), 8.20 (d, J=9 Hz, 1H, Ar), 8.65 (d, J=7.5 Hz, 1H,gluNH), 9.72 (s, 1H, Ar), 12.51 (br s, 1H, N²H). Mass spectrum (CI-CH₄):544 (M+1, 4.2%). Anal. Calculated for C₃₁H₃₃N₃O₆.1/10H₂O: C, 68.27; H,6.14; N, 7.70. Found: C, 68.34; H, 6.10; N, 7.68.

B.N-(4-(2-(1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)ethyl)benzoyl)-L-glutamicacid

¹H NMR (DMSO-d₆, 300 MHz) δ: 1.86-2.16 (m, 2H, gluCH₂), 2.35 (t, J=7.5Hz, 2H, gluCH₂), 2.43 (s, 3H, C₃—CH₃), 3.03-3.22 (m. 4H, ArCH₂'s),4.34-4.44 (m, 1H, gluCH), 7.40 (d, J=8 Hz, 2H, Ar), 7.54 (dd, J=8, 1.5Hz, 1H, Ar), 7.57 (d, J=8.5 Hz, 1H, Ar), 7.81 (d, J=8 Hz, 2H, Ar), 7.95(d, J=8, 5 Hz, 1H, Ar), 8.20 (d, J=9 Hz, 1H, Ar), 8.53 (d, J=7.5 Hz, 1H,gluNH), 9.72 (s, 1H, Ar), 12.15-12.6 (br s, 2H, CO₂H's), 12.51 (s, 1H,N²H). Anal. Calculated for C₂₇H₂₅N₃O₆.1/3H₂O: C, 65.72; H, 5.24; N,8.52. Found: C, 65.74; H, 5.22; N, 8.51.

An analog in which the linking aminomethylene moiety of the side chainwas replaced with a carbonamido-group was prepared as described below;

N-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)carbonyl)amino)benzoyl)-L-glutamicacid

A. DiethylN-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)carbonyl)amino)benzoyl)-L-glutamate

A solution of 9-bromo-3-methylbenzo[f]quinazolin-1(2H)-one (0.50 g, 1.7mmol) and cuprous cyanide (0.46 g, 5.1 mmol) in dimethylacetamide (10ml) under nitrogen was heated under reflux for 2 hours, cuprous cyanide(0.16 g, 1.8 mmol) added and refluxing continued for 18 hours. Thesolvent was removed under high vacuum to give crude9-cyano-3-methylbenzo[f]quinazolin-1(2H)-one. The solid was suspended insulphuric acid (2M, 300 ml), the suspension stirred at reflux undernitrogen for 40 hours, cooled and adjusted to pH 8.5 with sodiumhydroxide (21 g) and saturated sodium bicarbonate solution. Theresulting suspension was filtered to give the partially purified nitrilewhich was subjected to refluxing 2N hydrochloric acid in 95% ethanol for24 hours. The solution was made basic with NaOH, filtered, the filtrateadjusted to neutral and filtered. The resulting filtrate was adjusted topH 1.5 and the precipitate filtered and dried under high vacuum to givea 2:1 mixture of carboxylic acid to nitrile (225 mg). A solution of themixture (0.22 g), N-(4-aminobenzoyl)-L-glutamic acid diethyl ester (0.32g, 1.0 mmol), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimidehydrochloride (0.19 g, 1.0 mmol) in dimethylformamide (25 ml) wasstirred overnight, more 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimidehydrochloride (0.19 g, 1.0 mmol) added, the reaction mixture stirred foranother 4 hours, then concentrated in vacuo onto silica gel (2 g).Purification by chromatography on silica gel (150 g) eluting withmethanol:methylene chloride (3:97 to 1:19) and filtration of theresulting solid from methanol gave, after drying under high vacuum,diethyl(N-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)carbonyl)amino)benzoyl-L-glutamate(0.027 g). ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.18 (t, J=7 Hz, esterCH₃), 1.20(t, J=7 Hz, esterCH₃), 1.95-2.20 (m, 2H, gluCH₂), 2.46 (s, 3H, 3-CH₃ andt, J=7 Hz, 2H, gluCH₂), 4.06 (q, J=7 Hz, 2H, esterCH₂), 4.12 (q, J=6.5Hz, 2H, esterCH₂), 4.39-4.49 (m, 1H, gluCH), 7.75 (d, J=9 Hz, 1H, Ar),7.93 (s, 4H, Ar), 8.12 (dd, J=8.5, 1.5 Hz, 1H, Ar), 8.19 (d, J=8.5 Hz,1H, Ar), 8.35 (d, J=9 Hz, 1H, Ar), 8.67 (d, J=7.5 Hz, 1H, gluNH), 10.37(s, 1H, Ar), 10.76 (s, 1H, CONHAr), 12.72 (s, 1H, N²H). Exact massspectrum calculated for (C₃₀H₃₀N₄O₇)⁺: 559.2193. Found: 559.2191.

B.N-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)carbonyl)amino)benzoyl)-L-glutamicacid

¹H NMR (DMSO-d₆, 300 MHz) δ: 1.90-2.18 (m, 2H, gluCH₂, 2.39 (t, J=7.5Hz, 2H, gluCH₂), 2.47 (s, 3H, 3-CH₃), 4.37-4.47 (m, 1H, gluCH), 7.76 (d,J=7 Hz, 1H, Ar), 7.94 (s, 4H, Ar), 8.13 (dd, J=8.5, 1.5 Hz, 1H, Ar),8.20 (d, J=8.5 Hz, 1H, Ar), 8.35 (d, J=9 Hz, 1H, Ar), 8.56 (d, J=8 Hz,1H, gluNH), 10.38 (d, J=1 Hz, 1H, Ar), 10.76 (s, 1H, CONHAr), 12.1-12.7(v br s, 2H, CO₂H's), 12.72 (s, 1H, N²H). Anal. Calculated forC₂₆H₂₂N₄O₇.3/4H₂O: C, 60.52; H, 4.59; N, 10.86. Found: C, 60.55; H,4.54; N, 10.88.

Further variations in the side chain structure were effected bycondensation of the requisite p-aminobenzoate analog with3-methyl-9-bromomethylbenzo[f]quinazolin-1(2H)one; preparations of theside chain amines and data on the final products are given below.

4-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)phenyl)-4-oxobutyricacid

A. Ethyl-2-ethoxycarbonyl-4-(4-nitrophenyl)-4-oxobutyrate

To a solution of diethylmalonate (25 ml, 0.16 mole) in dimethylformamide(300 ml) was added sodium methoxide (8.6 g, 0.16 mole) and the solutionchilled in an ice bath. When temperature of the solution reach 10° C.,2-bromo-4′-nitroacetophenone (41 g, 0.16 mole) was added; after a fewminutes the reaction mixture was removed from the ice bath and stirredfor 2 hours. The solution was concentrated in vacuo, water (500 ml)added, and the mixture extracted with diethyl ether (250 and 150 ml).The combined ether extracts were washed with saturated sodium chloridesolution (100 ml), dried (MgSO₄), and concentrated in vacuo.Purification by chromatography on silica gel eluting with ethylacetate:hexane (1:4) gave ethyl2-ethoxycarbonyl-4-(4-nitrophenyl)-4-oxobutyrate (21.1 g) as an oil. ¹HNMR (DMSO-d₆, 300 MHz) δ: 1.20 (t, J=7 Hz, 6H, CH₃'s), 3.70 (d, J=7 Hz,2H, COCH₂), 3.96 (t, J=7 Hz, 1H, CH), 4.08-4.23 (m, 4H, esterCH₂'s),8.24 (d, J=9 Hz, 2H, Ar), 8.36 (d, J=9 Hz, 2H, Ar). Anal. Calculated forC₁₅H₁₇N₇.1/10H₂O: C, 55.42; H, 5.33; N, 4.31. Found: C, 55.44; H, 5.23;N, 4.27.

B. Ethyl 4-(4-nitrophenyl)-4-oxobutyrate

A solution of ethyl 2-ethyl2-ethoxycarbonyl-4-(4-nitrophenyl)-4-oxobutyrate (7.0 g, 22 mmol) andsulphuric acid (1.5 g) in acetic acid:water (20:1, 42 ml), was stirredat reflux for 4 hours and then allowed to stand for 60 hours at roomtemperature. The suspension was diluted with water (5 ml) and the solidfiltered, washed with water, and air dried. A solution of the solid inethanol (50 ml) containing a few drops of sulphuric acid was stirredovernight, then concentrated in vacuo. The residue was taken up indiethyl ether (75 ml), washed with saturated sodium bicarbonate solution(40 ml), dried (MgSO₄), and silica gel); concentration of the solutionin vacuo gave ethyl 4-(4-nitrophenyl)-4-oxobutyrate (1.4 g) as an oil.¹h NMR (DMSO-d₆, 300 MHz), δ: 1.18 (t, J=7 Hz, 3H, CH₃), 2.68 (t, J=6Hz, 2H, CH₂), 3.39 (t, J=6 Hz, 2H, CH₂), 4.07 (q, J=7 Hz, 2H, esterCH₂),8.22 (d, J=9 Hz, 2H, Ar), 8.36 (d, J=9 Hz, 2H, Ar). Anal. Calculated forC₁₂H₁₃NO₅: C, 57.37; H, 5.22; N, 5.58. Found: C, 57.44; H, 5.24; N,5.53.

C. Ethyl 4-(4-aminophenyl)-4-oxobutyrate

A solution of ethyl 4-(4-nitrophenyl)-4-oxobutyrate (1.4 g, 5.6 mmol)and 10% palladium on carbon (0.18 g) in ethanol (50 ml) was shaken underhydrogen (50 psi) for 2 hours then filtered and concentrated in vacuo.The residue was absorbed onto silica gel (5 g) from an ethyl acetatesolution and purified by chromatography on silica gel (100 g) elutingwith ethyl acetate:hexane (1:2) to give ethyl4-(4-aminophenyl)-4-oxobutyrate (0.38 g) as a white solid. ¹H NMR(DMSO-d₆, 300 MHz) δ: 1.17 (t, J=7 Hz, 3H, CH₃), 2.56 (t, J=6.5 Hz, 2H,CH₂), 3.10 (t, J=6.5 Hz, 2H, CH₂), 4.04 (q, J=7 Hz, 2H, esterCH₂), 6.04(br s, 2H, NH₂), 6.57 (d, J=9 Hz, 2H, Ar), 7.69 (d, J=9 Hz, 2H, Ar).Anal. Calculated for C₁₂H₁₅NO₃: C, 65.14; H, 6.83; N, 6.33. Found: C,65.23; H, 6.85; N, 6.32.

D.Ethyl-4-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)phenyl-4-oxobutyrate

¹H NMR (DMSO-d₆, 300 MHz) δ 1.17 (t, J=7 Hz, 3H, esterCH₃), 2.43 (s, 3H,C³—CH₃), 2.55 (t, J=6.5 Hz, 2H, CH₂), 3.09 (t, J=6.5 Hz, 2H, CH₂), 4.02(q, J=7 Hz, 2H, esterCH₂), 4.60 (d, J=5.5 Hz, 2H, C⁹—CH₂), 6.66 (d, J=9Hz, 2H, Ar), 7.34 (t, J=5.5 Hz, 1H, ArNH), 7.59 (d, J=8.5 Hz, 1H, Ar),7.61 (dd, J=8, 1.5 Hz, 1H), 7.71 (d, J=9 Hz, 2H, Ar), 8.00 (d, J=8,5 Hz,1H, Ar), 8.21 (d, J=8.5 Hz, 1H, Ar), 9.85 (s, 1H, Ar), 12.53 (s, 1H,N²H). Mass spectrum (CI-CH₄): 444 (M+1, 82.1%), 225 (100%), Anal.Calculated for C₂₆H₂₅N₃O₄.3/10H₂O: C, 69.57; H, 5.75; N, 9.36. Found: C,69.61; H, 5.75; N, 9.28.

E.4-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)phenyl)-4-oxobutyricacid

¹H NMR (DMSO-d₆, 300 MHz) δ: 2.43 (s, 3H, C³—CH₃), 2.50 (t, J=6.5 Hz,2H, CH₂), 3.04 (t, J=6.5 Hz, 2H, CH₂), 4.60 (d, J=6 Hz, 2H, C₉—CH₂),6.66 (d, J=9 Hz, 2H, Ar), 7.37 (t, J=6 Hz, 1H, ArNH), 7.59 (d, J=8.5 Hz,1H, Ar), 7.61 (dd, J=8.5, 1.5 Hz, 1H, Ar), 7.71 (d, J=9 Hz, 2H, Ar),8.00 (d, J=8.5 Hz, 1H, Ar), 8.21 (d, J=9 Hz, 1H, Ar), 9.85 (s, 1H, Ar),12.02 (s, 1H, CO₂H), 12.53 (s, 1H, N²H). Anal. Calculated forC₂₄H₂₁N₃O₄.3/4H₂O: C, 67.20; H, 5.29; N, 9.80. Found: C, 67.19; H, 5.24;N, 9.82.

Dodecyl4-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)phenyl)-4-oxobutyrate

A. 4-(4-nitrophenyl)-4-oxobutyric acid

A solution of ethyl 2-ethoxycarbonyl-4-(4-nitrophenyl)-4-oxobutyrate(6.2 g, 19 mmol) and sulphuric acid (1.0 g) in acetic acid:water (4:1,50 ml) was stirred at reflux for 4 hours, then concentracted in vacuo tosmall volume. Dilution with water (100 ml) gave a precipitate which wasfiltered and dried at 50° C. under vacuum. Purification bychromatography on silica gel eluting with methanol:methylene chloride(3:97) and filtration of the resulting solid from diethyl ethercontaining a small percentage of methanol gave, after drying under highvacuum, 4-(4-nitrophenyl)-4-oxobutyric acid (2.1 g). ¹H NMR (DMSO-d₆,300 MHz) δ: 2.62 (t, J=6 Hz, 2H, CH₂), 3.33 (t, J=6 Hz, 2H, CH₂), 8.22(d, J=8.5 Hz, 2H, Ar), 8.36 (d, J=8.5 Hz, 2H, Ar), 12.22 (s. 1H, CO₂H).Anal. Calculated for C₁₀H₉NO₅: C, 53.82; H, 4.06; N, 6.28. Found: C,53.65; H, 4.02; N, 6.21.

B. Dodecyl 4-(4-nitrophenyl)-4-oxobutyrate

A solution of 4-(4-nitrophenyl)-4-oxobutyric acid (0.50 g, 2.2 mmol),1-dodecanol (5.0 ml, 22 mmol), and p-toluenesulfonic acid (50 mg) intetrahydrofuran (2.5 ml) was stirred 60 hours at room temperature thenheated under reflux for 1.5 hours. Concentration of the reaction mixturein vacuo and purification by chromatography or silica gel (200 g)eluting with methylene chloride:hexane (1.1 to 2:1) followed byfiltration of the solid product from a small volume of hexane gave,after drying under high vacuum, dodecyl 4-(4-nitrophenyl)-4-oxobytyrate(0.43 g) as a white solid. ¹H NMR (DMSO-₆, 300 MHz) δ: 0.86 (t, J=6.5Hz, 3H, esterCH₃), 1.07-1.35 (m, 18H, esterCH₂'s), 1.47-1.60 (m, 2H,esterCH₂), 2.69 (t, J=6 Hz, 2H, CH₂), 3.39 (t, J=6 Hz, 2H, CH₂), 4.00(t, J=6.5 Hz, 2H, esterCH₂), 8.22 (d, J=9 Hz, 2H, Ar), 8.36 (d, J=9 Hz,2H, Ar). Anal. Calculated for C₂₂H₃₃NO₅: C, 67.49; H, 8.50; N, 3.58.Found: C, 67.36; H, 8.54; N, 3.55.

C. Dodecyl 4-(4-aminophenyl)-4-oxobutyrate

A solution of dodecyl 4-(4-nitrophenyl)-4-oxobutyrate (0.42 g, 1.1mmol), in ethyl acetate (50 ml) and 10% palladium on carbon (0.10 g)were shaken under hydrogen (30-40 psi) for 10 minutes. The mixture wasfiltered and the filtrate concentrated in vacuo to give dodecyl4-(4-aminophenyl)-4-oxobutyrate (0.38 g) as a white solid. ¹H NMR(DMSO-d₆, 300 MHz) δ: 0.86 (t, J=6.5 Hz, 3H, esterCH₃), 1.10-1.37 (m,18H, esterCH₂'s), 1.47-1.60 (m, 2H, esterCH), 2.57 (t, J=6.5 Hz, 2H,CH₂), 3.10 (t, J=6.5 Hz, 2H, CH₂), 3.98 (t, J=6.5 Hz, 2H, esterCH₂),6.04 (br s, 2H, NH₂), 6.56 (d, J=8.5 Hz, 2H, Ar), 7.68 (d, J=8.5 Hz, 2H,Ar). Anal. Calculated for C₂₂H₃₅NO₃.1/20H₂O: C, 72.91; H, 9.76; N, 3.86.Found: C, 72.86; H, 9.83; N, 3.82.

D. Dodecyl4-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)phenyl)-4-oxobutyrate

M.P.=213-214° C. ¹H NMR (DMSO-d₆, 300 MHz) δ 0.84 (t, J=6.5 Hz, 3H,esterCH₃), 1.07-1.33 (m, 18H, esterCH₂'s), 1.46-1.58 (m, 2H, esterCH₂),2.43 (s, 3H, C³—CH₃), 2.55 (t, J=6 Hz, 2H, CH₂), 3.09 (t, J=6 Hz, 2H,CH₂), 3.96 (t, J=6.5 Hz, 2H, esterCH₂), 4.60 (d, J=6 Hz, 2H, C₉—CH₂),6.66 (d, J=9 Hz, 2H, Ar), 7.38 (t, J=6 Hz, 1H, ArNH), 7.59 (d, J=8.5 Hz,1H, Ar), 7.61 (dd, J=8, 1.5 Hz, 1H, Ar), 7.71 (d, J=8.5 Hz, 2H, Ar),8.00 (d, J=8.5 Hz, 1H, Ar), 8.21 (d, J=9 Hz, 1H, Ar), 9.85 (s, 1H, Ar),12.53 (s, 1H, N²H). Mass spectrum (CI-CH₄): 584 (M+1, 1.2%). Anal.Calculated for C₃₆H₄₅N₃O₄: C, 74.07; H, 7.77; N, 7.20. Found: C, 74.11;H, 7.76; N, 7.25.

EthylN-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)glycinate

A. Ethyl N-(2-fluoro-4-nitrobenzoyl)glycinate

Triethylamine (0.85 ml, 6.1 mmol) was added to a solution of2-fluoro-4-nitrobenzoic acid (T. R. Jones et al., UK Patent GB 2175903A, 1986) (1.0 g, 5.4 mmol), glycine ethyl ester hydrochloride (0.85g, 6.1 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.1 g, 5.7 mmol) in methylene chloride (30 ml). Afterstirring 1 hour at room temperature the solution was passed through ashort pad of silica gel eluting with ethyl acetate:methylene chloride(1:3) and the resulting white solid was filtered from hexane and driedunder high vacuum to give ethyl N-(2-fluoro-4-nitrobenzoyl)glycinate(1.04 g). ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.22 (t, J=7 Hz, 3H, CH₃), 4.05(d, J=6 Hz, 2H, glyCH₂), 4.15 (q, J=7 Hz, 2H, esterCH₂), 7.88 (t, J=8Hz, 1H, Ar), 8.17 (dd, J=8.5, 1.5 Hz, 1H, Ar), 8.25 (dd, J=10, 2 Hz,1H), 9.09 (br t, J=5.5 Hz, 1H, CONH). Anal. Calculated for C₁₁H₁₁FN₂O₅:C, 48.89; H, 4.10; N, 10.37. Found: C, 49.00; H, 4.11; N, 10.43.

B. Ethyl N-(4-amino-2-fluorobenzoyl)glycinate

A solution of ethyl N-(2-fluoro-4-nitrobenzoyl)glycinate (0.40 g, 1.5mmol) and 10% palladium on carbon (0.10 g) in ethanol (25 ml) was shakenunder hydrogen (30-40 psi) for 1.5 hours. The solution was filtered andconcentrated in vacuo to give N-(4-amino-2-fluorobenzoyl)glycinate as asolid (0.34 g). ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.20 (t, J=7.1 Hz, 3H,CH₃), 3.95 (d, J=5.7 Hz, 2H, glyCH₂), 4.11 (q, J=7.1 Hz, 2H, esterCH₂),6.03 (br s, 2H, NH₂), 6.32 (dd, J=14.6, 2.0 Hz, 1H, Ar), 6.41 (dd,J=8.6, 2.0 Hz, 1H, Ar), 7.50 (t, J=8.8 Hz, 1H, Ar), 7.92 (dd, J=6.5,5.9H₂, 1H, CONH). Anal. Calculated for C₁₁H₁₃FN₂O₃: C, 55.00; H, 5.45;H, 11.66. Found: C, 55.08; H, 5.45; N, 11.63.

C. EthylN-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)glycinate

¹H NMR (DMSO-d₆, 300 MHz) δ: 1.19 (t, J=7.1 Hz, 3H, esterCH₃), 2.43 (s,3H, C³—CH₃), 3.93 (d, J=5.6 Hz, 2H, glyCH₂), 4.09 (q, J=7.1 Hz, 2H,esterCH₂), 4.57 (d, J=5.6 Hz, 2H, C⁹—CH₂), 6.40 (dd, J=14.9, 1.6 Hz, 1H,Ar), 6.54 (dd, J=8.7, 1.9 Hz, 1H, Ar), 7.34 (t, J=5.7 Hz, 1H, ArNH),7.52 (t, J=8.9 Hz, 1H, Ar), 7.60 (d, J=8.8 Hz, 1H, Ar), 7.62 (t, J=8.9Hz, 1H, Ar), 7.95 (dt, J=6.5, 5.8 Hz, 1H, CONH), 8.02 (d, J=8.3 Hz, 1H,Ar), 8.22 (d, J=8.9 Hz, 1H, Ar), 9.85 (s, 1H, Ar), 12.55 (s, 1H, N²H).Mass spectrum (CI-CH₄): 463 (M+1, 100%). Anal. Calculated forC₂₅H₂₃FN₄O₄.2/5H₂O: C, 63.93; H, 5.11; J, 11.93. Found: C, 63.89: H,5.08; N, 11.93.

N-((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-N-(2-hydroxyethyl)benzamide

A. 4-Amino-N-(2-hydroxyethyl)benzamide

A solution of 4-aminobenzoic acid (2.7 g, 20 mmol), ethanolamine (1.4 g,23 mmol), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimidehydrochloride (4.1 g, 21 mmol) in dimethylformamide (60 ml) was stirredovernight at room temperature. More carbodiimide (0.3 g, 2 mmol) wasadded and after stirring for one hour the reaction mixture wasconcentrated in vacuo onto silica gel (15 g). Purification bychromatography on silica gel (125 g) eluting with methanol:methylenechloride (3:97 to 1:19) and recrystallization from methanol:ethylacetate gave, after drying under high vacuum,4-amino-N-(2-hydroxyethyl)benzamide (1.65 g) as a white solid. ¹H NMR(DMSO-d₆, 300 MHz) δ: 3.26 (q, J=6 Hz, 2H, NCH₂), 3.46 (q, J=6 Hz, 2H,OCH₂), 4.68 (t, J=5.5, 1H, OH), 5.58 (br s, 2H, NH₂), 6.51 (d, J=8.5 Hz,2H, Ar), 7.56 (d, J=8.5 Hz, 2H, Ar), 7.94 (br t, J=5.4 Hz, 1H, CONH).Mass spectrum (CI-CH₄): 181 (M+1, 100%). Anal. Calculated for C₉H₁₂N₂O₂:C, 59.99; H, 6.71; N, 15.55. Found: C, 60.05; H, 6.72; N, 15.55.

B.N-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-N-(2-hydroxyethyl)benzamide

¹H NMR (DMSO-d₆, 300 MHz) δ: 2.43 (s, 3H, C³—CH₃), 3.21-3.30 (m, 2H,NCH₂), 3.41-3.49 (m, 2H, OCH₂), 4.55 (d, J=6 Hz, 2H, C⁹—CH₂), 4.68 (t,J=5.5 Hz, 1H, OH), 6.62 (d, J=8.5 Hz, 2H, Ar), 6.94 (t, J=6 Hz, 1H,ArNH), 7.55-7.64 (m, 4H, Ar), 7.96 (t, J=5.5 Hz, 1H, CONH), 7.99 (d,J=8.5 Hz, 1H, Ar), 8.21 (d, J=9 Hz, 1H, Ar), 9.84 (s, 1H, Ar), 12.53 (s,1H, N²H). Mass spectrum (CI-CH₄): 403 (M+1, 71.6%), 342 (100%). Anal.Calculated for C₂₃H₂₂N₄O₃.4/3H₂O: C, 64.79; H, 5.83; N, 13.14. Found: C,64.82; H, 5.71; N, 13.12.

N-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-8-yl)methyl)amino)benzoyl)-L-glutamicacid an analog in which the sidechain is attached to the 8-position ofthe benzoquinazoline nucleus, was prepared by a sequence of reactionsessentially similar to those described above.

A. 5,6-Dihydro-3.8-dimethylbenzo[f]quinazolin-1(2H)-one was preparedfrom 4′-methylphenylacetic acid as described in Example A(Method B).

¹H NMR (DMSO-d₆, 200 MHz) δ: 2.26 (s, 3H, CH₃), 2.27 (s, 3N, CH₃),2.60-2.84 (m, 4H, ArCH₂'s), 6.95-7.05 (m, 2H, Ar), 8.43 (d, J=8.4 Hz,1H, Ar), 12.49 (br s, 1H, N²H). Anal. Calculated for C₁₄H₁₄H₂O: C,74.31; H, 6.24; N, 12.38. Found: C, 74.25; H, 6.27; N, 12.31.

B. 3.8-Dimethylbenzo[f]quinazolin-1(2H)-one was prepared from theforegoing dihydro-derivative as described in Example 5.

¹H NMR (DMSO-d₆, 200 MHz) δ: 2.40 (s, 3H, CH₃), 2.49 (s, 3H, CH₃), 7.54(dd, J=8.7, 1.8 Hz, 1H, Ar), 7.57 (d, J=8.8 Hz, 1H, Ar), 7.79 (s, 1H,Ar), 8.13 (d, J=8.7 Hz, 1H, Ar), 9.68 (d, J=8.8 Hz, 1H, Ar), 12.49 (brs, 1H, 2-NH). Anal. Calculated for C₁₄H₁₂N₂O: C, 74.98; H, 5.39; N,12.49. Found: C, 74.85; H, 5.44; N, 12.41.

C.N-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-8-yl)methyl)amino)benzoyl)-L-glutamicacid was made from the foregoing dimethyl benzoquinazoline essentiallyas described for the 9-isomer above. Physical and analytical data on theproduct and the glutamate diester intermediate are given below.

DiethylN-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-8-yl)methyl)amino)benzoyl-L-glutamate

¹H NMR (DMSO-d₆, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H, esterCH₃), 1.17 (t,J=7 Hz, 3H, esterCH₃), 1.86-2.14 (m, 2H, gluCH₂), 2.39 (t, J=7 Hz, 2H,gluCH₂), 2.43 (s, 3H, C³—CH₃), 4.03 (q, J=7 Hz, 2H, esterCH₂), 4.07 (m,2H, gluCH₂), 4.31-4.40 (m, 1H, gluCH), 4.55 (d, J=6 Hz, 1H, C⁸CH₂), 6.64(d, J=9 Hz, 2H, Ar), 6.99 (t, J=6 Hz, 1H, ArNH), 7.60 (d, J=8.7 Hz, 1H,Ar), 7.63 (d, J=8.5 Hz, 2H, Ar), 7.73 (dd, J=8.8, 2 Hz, 1H, Ar), 7.97(s, 1H, Ar), 8.19 (d, J=8 Hz, 1H, Ar), 8.21 (d, J=7.5 Hz, 1H, gluNH),9.77 (d, J=8.8 Hz, 1H, Ar), 12.53 (br s, 1H, N²H). Anal. Calculated forC₃₀H₃₂N₄O₆.17/20H₂O: C, 64.35; H, 6.07; N, 10.01. Found: C, 64.38; H,6.08; N, 10.04.

N-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-8-yl)methyl)amino)benzoyl)-L-glutamicacid

¹H NMR (DMSO-d₆, 300 MHz) δ: 1.82-2.10 (m, 2H, gluCH₂), 2.31 (t, J=7.3Hz, 2H, gluCl₂), 2.44 (m, 3H, C³—CH₃), 4.28-4.38 (m, 1H, gluCH), 4.55(br s, 2H, C⁸—CH₂), 6.65 (d, J=8.7 Hz, 2H, Ar), 6.98 (br s, 1H, ArNH),7.61 (d, J=9 Hz, 1H, Ar), 7.64 (d, J=9 Hz, 2H, Ar), 7.74 (dd, J=8.8, 2Hz, 1H, Ar), 7.97 (d, J=1 Hz, 1H, Ar), 8.10 (d, J=7.6 Hz, 1H, gluNH),8.21 (d, J=8.9 Hz, 1H, Ar), 9.77 (d, J=8.8 Hz, 1H, Ar), 12.30 (br s, 2H,CO₂H's), 12.55 (br s, 1H, N²H). Anal. Calculated for C₂₆H₂₄N₄O₆.H₂O: C,61.65; H, 5.17; N, 11.06. Found: C, 61.65; H, 5.19; N, 11.00.

EXAMPLE 359-((4-Acetylanilino)methyl)-3-methylbenzo[f]quinazolin-1(2H)-one

9-Bromomethyl-3-methylbenzo[f]quinazolin-1(2H)-one (1 g, 3.3 mmole) and4-aminoacetophenone (0.89 g, 6.6 mmole) (Aldrich) were dissolved indimethylformamide (15 ml). The solution was stirred under nitrogen at100° C. for 30 min. Sodium bicarbonate (0.55 g, 6.6 mmole) was added andstirring was continued for a further 30 min. Dimethylformamide wasremoved in vacuo, the residue triturated with water and the solidcollected by filtration. The dried solid was subjected to chromatographyon silica (methanol/methylene chloride (1:19)). Fractions containingproduct were concentrated until solid began to precipitate. The solutionwas chilled at 50° C. for 12 hours, then the solid filtered off anddried under high vacuum to yield the title compound (0.48 g, 41%).Mp>235° C. ¹H NMR (DMSO-d₆, 300 MHz) δ: 2.37 (s, 3H, CH₃); 2.43 (s, 3H,CH₃); 4.59 (d, J=6 Hz, 2H, CH₂); 6.65 (d, J=9 Hz, 2H, Ar); 7.37 (t, J=6Hz, 1H, ArNH); 7.59 (d, J=9 Hz, 1H, Ar); 7.61 (dd, J=8, 2 Hz, 1H, Ar);7.69 (d, J=9 Hz, 2H, Ar); 8.00 (d, J=8 Hz, 1H, Ar); 8.21 (d, J=9 Hz, 1H,Ar); 9.85 (s, 1H, Ar); 12.52 (s, 1H, NH). Anal Calculated forC₂₂H₁₉N₃O₂.1/2H₂O: C, 72.11; H, 5.50; N, 11.47. Found: C, 72.26; H,5.46; N, 11.35.

3-Methyl-9-((4-(trifluoromethyl)anilino)methyl)benzo[f]quinazolin-1(2H)-onewas similarly prepared from 4-trifluoromethylaniline

¹H NMR (DMSO-d₆, 300 MHz) δ: 2.43 (s, 3H, CH₃), 4.56 (d, J=6 Hz, 2H,ArCH₂), 6.72 (d, J=9 Hz, 2H, Ar), 7.17 (t, J=6 Hz, 1H, ArNH), 7.35 (d,J=9 Hz, 2H, Ar), 7.59 (d, J=9 Hz, 1H, Ar), 7.62 (dd, J=8, 2 Hz, 1H, Ar),8.00 (d, J=8 Hz, 1H, Ar), 8.21 (d, J=9 Hz, 1H, Ar), 9.85 (s, 1H, Ar),12.54 (br s, 1H, N²H). Mass spectrum (CI-CH₄): 384 (M+1, 13.9%), 383 (M,23.9%), 364 (100%). Anal. Calculated for C₂₁H₆F₃N₃O: C, 65.79; H, 4.21;N, 10.96. Found: C, 65.71; H, 4.22; N, 10.90.

3-Methyl-9-((4-nitroanilino)methyl)benzo(f)quinazolin-1(2H)-one wassimilarly prepared from 4-nitroaniline. ¹H NMR (DMSO-d₆, 300 MHz) δ:2.43 (s, 3H, CH₃); 4.66 (d, J=6 Hz, 2H, ArCH₂); 6.72 (d, J=9 Hz, 2H,Ar); 760 (d, J=9 Hz, 1H, Ar); 7.58-7.61 (m, 1H, Ar); 7.97-8.03 (m, 1H,Ar); 7.98 (d, J=9 Hz, 2H, Ar); 8.22 (d, J=9 Hz, 1H, Ar); 9.84 (s, 1H,Ar); 12.53 (s, 1H, NH). Mass Spectrum (CI-CH₄): 361 (M+1, 100%). Anal.Calculated for C₂₀H₁₆N₄O₃.1/4H₂O: C, 66.21; H, 4.74; N, 15.07. Found: C,66.24; H, 4.63; N, 14.95.

4-(((1,2-Dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methyl)amino)benzonitrilewas similarly prepared from 4-aminobenzonitrile. ¹H NMR (DMSO-d₆, 300MHz) δ: 2.43 (s, 3H, CH₃); 4.57 (d, J=6 Hz, 2H, ArCH₂); 6.70 (d, J=9 Hz,2H, Ar); 7.43 (d, J=9 Hz, 1H, Ar); 7.42-7.46 (m, 1H, Ar); 7.59 (m, 1H,Ar); 8.00 (d, J=8 Hz, 1H, Ar); 8.21 (d, J=9 Hz, 1H, A ; 9.84 (s, 1H,Ar); 12.53 (s, 1H, NH). Mass Spectrum (CI-CH₄): 341 (M+1,29.84%), 74(100%). Anal. Calculated for C₂₁H₁₆N₄O: C, 74.10; H, 4.74; N, 16.46.Found: C, 74.03; H, 4.77; N, 16.40.

3-Methyl-9-(anilinomethyl)benzo(f)quinazoline-1(2)-one was similarlyprepared from aniline. ¹H NMR (DMSO-₆, 300 MHz) δ: 2.43 (s, 3H, CH₃);4.49 (d, J=5.9 Hz, 2H, ArCH₂); 6.39 (t, J=5.9 Hz, 1H, NH); 6.50 (t,J=7.3 Hz, 1H, Ar); 6.61 (dd, J₁=1 Hz, J₂=8.6 Hz, 2H, Ar); 7.03 (dd,J₁=8.5 Hz, J₂=7.3 Hz, 2H, Ar); 7.58 (d, J=8.7 Hz, 1H, Ar); 7.64 (dd,J₁=1.6 Hz, J₂=8.3 Hz, 1H, Ar); 7.99 (d, J=8.2 Hz, 1H, Ae); 8.20 (d,J=8.7 Hz, 1H, Ar); 9.85 (s, 1H, Ar); 12.52 (br s, J=8.2 Hz, 1H, NH).Mass Spectrum (CI-CH₄): 316 (M+1, 52.80%), 223 (100%). Anal. Calculatedfor C₂₀H₁₇N₃O: C, 76.17; H, 5.43; N, 13.22. Found C, 76.15; H, 5.48; N,13.24.

9-((4-Methoxyanilino)methyl)-3-methylbenzo(f)quinazolin-1(2H)-one wassimilarly prepared from p-anisidine. ¹H NMR (DMSO-d₆, 300 MHz) δ: 2.43(s, 3H, CH₃); 3.60 (s, 3H, CH₃): 4.43 (d, J=6 Hz, 2H, ArCH₂); 5.97 (t,J=6 Hz, 1H, NH); 6.57 (d, J=9 Hz, 2H, Ar); 6.68 (d, J=9 Hz, 2H, Ar);7.58 (d, J=9 Hz, 1H, Ar); 7.64 (dd, J₁=1 Hz, J₂=8 Hz, 1H, Ar); 7.99 (d,J=9 Hz, 1H, Ar); 8.20 (d, J=9 Hz, 1H, Ar); 9.84 (s, 1H, Ar); 12.52 (brs, J=8.2 Hz, 1H, NH). Mass Spectrum (CI-CH₄): 346 (M+1, 100%). Anal.Calculated for C₂₁H₁₉N₃O₂.3/10H₂O: C, 71.90; H, 5.63; N, 11.98. Found:C, 71.92; H, 5.55; N, 11.97.

9-((3-Chloroanilino)methyl)-3-methylbenzo(f)quinazolin-1(2H)-one wassimilarly prepared from 3-chloroaniline. ¹H NMR (DMSO-d₆, 200 MHz) δ:2.40 (s, 3H, CH₃); 4.47 (d, J=5.7 Hz, 2H, ArCH₂); 6.46-6.60 (m, 3H, Ar),6.74 (t, J=5.7 Hz, 1H, NH); 7.01 (t, J=8 Hz, 1H, Ar); 7.54-5.62 (m, 2H,Ar); 7.98 (d, J=8.4 Hz, 1H, Ar); 8.19 (d, J=8.9 Hz, 1H, Ar); 9.82 (s,1H, Ar); 13.40 (s, 1H, NH). Mass Spectrum (CI-CH₄): 350 (M+1, 17.93%),223 (100%). Anal. Calculated for C₂₀H₁₆CIN₃O: C, 68.67; H, 4.61; N,12.01; Cl, 10.13. Found: C, 68.51; H, 4.65; N, 11.93; Cl, 10.01.

9-((2-Fluoroanilino)methyl)-3-methylbenzo(f)quinazolin-1(2H)-one wassimilarly prepared from 2-fluoroaniline. ¹H NMR (DMSO-d₆, 200 MHz) δ:2.40 (s, 3H, CH₃); 4.54 (t, 5.9 Hz, 2H, ArCH₂); 6.31 (t, J=4.2 Hz, 1H,NH); 6.41-6.59 (m, 2H, Ar); 6.80 (t, J=7.8 Hz, 1H, Ar); 6.99 (ddd,J₁=12.2 Hz, J₂=7.8 Hz, J₃=1.3 Hz, 1H, Ar); 7.56 (d, J=8.8 Hz, 1H, Ar);7.60 (dd, J₁=8.2 Hz, J₂=1.3 Hz, 1H, Ar); 7.94 (d, J=8.4 Hz, 1H, Ar);8.15 (d, J=8.8 Hz, 1H, Ar); 9.82 (s, 1H, Ar); 12.48 (br s, 1H, NH). MassSpectrum (CI-CH₄): 334. (M+1, 54.42%), 223 (100%). Anal. Calculated forC₂₀H₁₆FN₃O.C₂H₄O₂: C, 67.17; H, 5.12; N, 10.68. Found: C, 67.17; H,5.31; N, 10.64.

9-((3,4-Difluoroanilino)methyl)-3-methylbenzo(f)quinazolin-1(2H)-one wassimilarly prepared from 3,4-difluoroaniline. ¹H NMR (DMSO-d₆, 200 MHz)δ: 2.40 (s, 3H, CH₃); 4.44 (d, J=6 Hz, 2H, ArCH₂); 6.32-6.40 (m, 1H,NH); 6.48-6.61 (m, 2H, Ar); 7.05 (ddd, J₁=19.2 Hz, J₂=9.9 Hz, J₃=1.4 Hz,1H, Ar); 7.58 (d, J=8.7 Hz, 1H, Ar); 7.59 (dd, J₁=8.3 Hz, J₂=1.6 Hz, 1H,Ar); 7.98 (d, J=8.3 Hz, 1H, Ar); 8.18 (d, J=8.6 Hz, 1H, Ar); 9.81 (s,1H, Ar); 12.48 (br s, 1H, NH). Mass Spectrum (CI-CH₄): 352 (M+1,28.42%). 223 (100%). Anal. Calculated for C₂₀H₁₅F₂N₃O C₂H₄O₂: C, 68.37;H, 4.30; N, 11.96. Found: C, 68.26; H, 4.35; N, 11.90.

3-Methyl-9-(((1oxo-5-indahyl)amino)methyl)benzo[f]quinazolin-1(2H)-onewas similarly prepared from 5-amino-1-indanone (J. Org. Chem., 1962, 27,70). ¹H NMR (DMSO-d₆, 300 MHz) δ: 2.37-2.48 (m, 2H, CH₂), 2.43 (s, 3H,CH₃), 2.82-2.92 (m, 2H, CH₂), 4.61 (d, J=5.5 Hz, 2H, ArCH₂N), 6.60 (s,1H, Ar), 6.69 (dd, J=8.5, 1.5 Hz, 1H, Ar); 7.33 (d, J=8.5 Hz, 1H, Ar),7.51 (t, J=6 Hz, 1H, ArNH), 7.60 (d, J=9 Hz, 1H, Ar), 7.62 (dd, J=8.5,1.5 Hz, 1H, Ar), 8.01 (d, J=8.5 Hz, 1H, Ar), 8.22 (d, J=9 Hz, 1H, Ar),9.86 (s, 1H, Ar), 12.54 (s, 1H, N²H). Mass Spectrum (CI-CH₄): 370 (M+1,100%). Anal. Calculated for C₂₃H₁₉N₃O₂.3/10H₂O: C, 73.70; H, 5.27; N,11.21. Found: C, 73.78; H, 5.28; N, 11.21.

Ethyl4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)benzoatewas similarly prepared from ethyl 4-aminobenzoate.

¹H NMR (DMSO-d₆, 300 MHz) δ: 1.25 (t, J=7 Hz, 3H, esterCH₃), 2.43 (s,3H, C³—CH 3), 4.19 (q, J=7 Hz, 2H, esterCH₂), 4.58 (br d, J=6 Hz, 2H,C₉—CH₂), 6.66 (d, J=9 Hz, 2H, Ar), 7.28 (br t, J=6 H, 1H, ArNH), 7.59(d, J=8.5 Hz, 1H, Ar), 7.61 (dd, J=8, 1.5 Hz, 1H, Ar), 7.66 (d, J=9 Hz,2H, Ar, 8.00 (d, J=8.5 Hz, 1H, Ar), 8.21 (d, J=9 Hz, 1H, Ar), 9.84 (s,1H, Ar), 12.53 (s, 1H, N²H). Mass Spectrum (CI-CH₄): 388 (M+1, 44.2%),387 (M, 24.2%), 342 (100%). Anal. Calculated for C₂₃H₂₁N₃O₃.1/5H₂O: C,70.65; H, 5.52; N, 10.75. Found: C, 70.65; H, 5.49; N, 10.77.

4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)benzoicacid was prepared by hydrolysis of the foregoing ester under conditionsessentially similar to those described for the p-aminobenzoylglutamateesters.

¹H NMR (DMSO-d₆/D₂O, 300 MHz) δ: 2.43 (s, 3H, C³—CH₃), 4.56 (s, 2H,C⁹—CH₂), 6.64 (d, J=9 Hz, 2H, Ar), 7.55-7.67 (m, 4H, Ar), 8.00 (d, J=Hz,1H, Ar), 8.22 (d, J=9 Hz, 1H, Ar), 9.83 (s, 1H, Ar). Mass Spectrum(CI-CH₄): 359 (M, 25.9%). Anal. Calculated for C₂₁H₁₇N₃O₃.7/6H₂O: C,66.31; H, 5.12; N, 11.05. Found: C, 66.24; H, 5.13; N, 11.06.

4-((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)oxy)benzonitrile

A. Ethyl-3-(4-cyanophenyloxy)phenylacetate

A solution of ethyl 3-hydroxyphenylacetate (28 g, 0.15 mole) and4-fluorobenzonitrile (25 g, 0.21 mole) in dimethylsulfoxide (150 ml) wasstirred with 87% potassium hydroxide (10 g, 0.15 mole) at 75-80° C. for80 minutes under nitrogen. The resulting mixture was allowed to cool,diluted with water (1000 ml), and extracted with diethyl ether (2×50ml). The organic solution was washed with water (100 ml), dried (MgSO₄),concentrated in vacuo and the residue eluted on silica gel (500 g) withethyl acetate:hexane (0 to 1:6). A solution of the product in diethylether (125 ml) was washed with 1N NaOH (15 ml) to remove some residualphenol, dried (K₂CO₃ and MgSO₄), and concentrated in vacuo to give ethyl3-(4-cyanophenyloxy)phenylacetate (20.8 g). ¹H NMR (DMSO-d₆, 300 MHz) δ:1.18 (t, J=7 Hz, 3H, CH₃), 3.71 (s, 2H, Ar CH₂), 4.08 (q, J=7 Hz, 2H,esterCH₂), 7.02-7.13 (m, 4H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.42 (t, J=8Hz, 1H, Ar), 7.85 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C₁₇H₁₅NO₃:C, 72.58: H, 5.37; N, 4.98. Found: C, 72.67; H, 5.43; N, 4.94.

B. 3-(4-Cyanophenyloxy)phenylacetic acid

A solution of ethyl 3-4(4-cyanophenyloxy)phenylacetate (20.8 g, 74 mmol)in methanol:1N sodium hydroxide (1:1, 160 ml) was stirred at reflux for1.5 hours, IN sodium hydroxide (5 ml) added and refluxing continued forone hour. The solution was cooled and acidified with 2N hydrochloricacid (45 ml), the resulting suspension chilled in an ice bath, and theproduct filtered, washed with water and dried at 70° C. under vacuum togive 3-(4-cyanophenyloxy)phenylacetic acid (17.1 g). ¹H NMR (DMSO-d₆,300 MHz) δ: 3.62 (s, 2H, CH₂), 7.00-7.14 (m, 4H, Ar), 7.17 (d, J=8 Hz,1H, Ar), 7.41 (t, J=8 Hz, 1H, Ar), 7.85 (d, J=9 Hz, 2H, Ar), 12.39 (brs, 1H, CO₂H). Anal. Calculated for C₁₅H₁₁NO₃.1/25H₂O: C, 70.94; H, 4.40;N, 5.51. Found: C, 71.01; H, 4.40; N, 5.45.

C.4-((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)oxy)benzonitrilewas prepared from 3-(4-cyanophenyloxy)phenylacetic acid by the sequenceessentially described in Examples A, 3 and 5.

¹H NMR (DMSO-d₆, 300 MHz) δ: 2.44 (s, 3H, CH₃), 7.21 (AA′BB′, 2H, Ar),7.48 (dd, J=9.3 Hz, 1H, Ar), 7,63 (d, J=9 Hz, 1H, Ar), 7.88 (AA′BB′, 2H,Ar), 8.17 (d, J=9 Hz, 1H, Ar), 8.31 (d, J=9 Hz, 1H, Ar), 9.55 (d, J=3Hz, 1H, Ar), 12.58 (br s, 1H, N²H). Anal. Calculated for C₂₀H₁₃N₃O₂: C,73.39, H, 4.00; N, 12.84. Found: C, 73.27; H, 4.05; N, 12.75.

EXAMPLE 36N-(4-((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoyl)-L-glutamicacid

A. 3,9-Dimethyl-2-methoxymethylbenzo[f]quinazolin-1(2H)-one

To a suspension of 3,9-dimethylbenzo[f]quinazolin-1(2H)-one (1.0 g, 4.5mmol) in DMF (25 ml) was added 80% NaH (0.15 g, 5.0 mmol) (Aldrich)portion wise and the mixture was stirred 35 minutes. Bromomethyl methylether (0.39 ml, 4.8 mmol) (Aldrich) was added in one portion and thesolution was stirred at room temperature overnight. The solution wasthen diluted with water (100 ml) and extracted twice with methylenechloride (100, 40 ml). The combined methylene chloride extracts werewashed with a small volume of water, dried (K₂CO₃), and concentrated invacuo. The residue was purified by silica gel (40 g) chromatographyeluting with ethyl acetate:methylene chloride (0 to 1:19) to give3,9-dimethyl-2-methoxymethylbenzo[f]quinazolin-1(2H)-one and thecorresponding O-alkylated material in a 4:1 ratio as determined by NMR(0.79 g). ¹H NMR (DMSO-d₆, 300 MHz) for major isomer δ: 2.57 (s, 3H,C⁹—CH₃), 2.68 (s, 3H, C³—CH₃), 3.38 (s, 3H, OCH₃), 5.62 (s, 2H, NCH₂O),7.51 (dd, J=8, 2 Hz, 1H, Ar), 7.56 (d, J=9 Hz, 1H, Ar), 7.96 (d, J=8 Hz,1H, Ar), 8.24 (d, J=9 Hz, 1H, Ar), 9.63 (s, 1H, Ar). Anal. Calculatedfor C₁₆H₆N₂O₂: C, 71.62; H, 6.01; H, 10.44. Found: C, 71.55; H, 6.03; H,10.43.

B. Ethyl4-((1,2-dihydro-2-methoxymethyl-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoate

N-bromosuccinimide (0.50 g, 2.8 mmol) (Kodak) was added to a hotsolution of the protected 3,9-dimethylbenzo[f]quinazoline (0.75 g, 2.8mmol) in benzene (100 ml) under nitrogen. The solution was stirred atreflux for 45 minutes and then concentrated in vacuo to give9-bromomethyl-2-methoxymethyl-3-methylbenzo[f]quinazolin-1(2H)-one asthe major product. NaH (80%, 0.25 g, 8.3 mmol) was added portion wise toa solution of ethyl p-hydroxybenzoate (1.4 g, 8.4 mmol) (Eastman) in DMF(10 ml) and stirred 30 minutes. The crude9-bromomethyl-2-methoxymethyl-3-methylbenzo[f]quinazolin-1(2H)-one wasadded with more DMF (10 ml) and the reaction mixture stirred 2.5 hoursat 35° C. and briefly heated to 90° C. After cooling, the solution wasdiluted with water (100 ml) and extracted with methylene chloride:ethylacetate (2:1, 2×150 ml). The extracts were washed with water (100 ml),dried (K₂CO₃), and concentrated in vacuo. The residue was purified bychromatography on silica gel (100 g) eluting with ethylacetate:methylene chloride (0 to 3:17). The solid was recrystallizedfrom a small volume of ethanol and dried under high vacuum to give ethyl4-((1,2-dihydro-2-methoxymethyl-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxybenzoate(0.235 g). ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.31 (t, J=7 Hz, 3H, esterCH₃),2.70 (s, 3H, C³—CH₃), 3.39 (s, 3H, OCH₃), 4.28 (q, J=7 Hz, 2H,esterCH₂), 5.45 (s, 2H, C⁹—CH₂O), 5.63 (s, 2H, NCH₂O), 7.20 (d, J=9 Hz,2H, Ar), 7.66 (d, J=9 Hz, 1H, Ar), 7.76 (dd, J=8, 2 Hz, 1H, Ar), 7.94(d, J=9 Hz, 2H, Ar), 8.11 (d, J=8 Hz, 1H, Ar), 8.32 (d, J=9 Hz, 1H, Ar),9.92 (s, 1H, Ar). Anal. Calculated for C₂₅H₂₄N₂O: C, 69.43; H, 5.59; N,6.48. Found: C, 69.32; H, 5.61; N, 6.41.

C. 4-((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoicacid

A solution of ethyl4-((1,2-dihydro-2-methoxymethyl-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoatein THF:1N HCl: concentrated HCl (15:10:1, 26 ml) was stirred at 60° C.overnight. The resulting suspension was diluted with water, concentratedin vacuo to remove the THF, and chilled in an ice bath. The solid wasfiltered, washed with water, and dried in vacuo at 100° C. The resultingester was dissolved in 1N NaOH (10 ml) and ethanol (^(˜)3 ml) andstirred at 60° C. for 4 hours. The solution was acidified withconcentrated HCl to pH 1.5 and the resulting precipitate filtered anddried in vacuo at 110° C. to give4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoicacid (0.195 g). ¹H NMR (DMSO-d₆, 300 MHz) δ: 2.59 (s, 3H, CH₃), 5.46 (s,2H, CH₂O), 7.17 (d, J=9 Hz, 2H, Ar), 7.80 (overlapping d, J=9 Hz, 2H,Ar), 7.91 (d, J=9 Hz, 2H, Ar), 8.16 (d, J=8 Hz, 1H, Ar), 9.85 (s, 1H,Ar).

D. DiethylN-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoyl)-L-glutamate

To a stirred suspension of4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoicacid (0.19 g, 0.53 mmol) and L-glutamic acid diethyl ester hydrochloride(0.14 g, 0.58 mmol) (Aldrich) in DMF (3 ml) were added diethylcyanophosphonate (0.09 ml, 0.6 mmol) (Aldrich) and triethylamine (0.15ml, 1.1 mmol). Additional DMF (7 ml) was added but homogeneous solutionwas not obtained. The reaction mixture was stirred 45 minutes at roomtemperature and TLC analysis indicated remaining benzoic acid. Diethylcyanophosphonate (2 drops) was added, the mixture stirred 45 minutes,and was then concentrated in vacuo. The residue was purified bychromatography on silica gel (50 g) eluting with ethanol:methylenechloride (1:9). The solid was filtered from a small volume of ethanoland dried under reduced pressure to give diethylN-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoyl)-L-glutamate(0.187 g). ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.16 (t, J=7 Hz, 3H, esterCH₃),1.18 (t, J=7 Hz, 3H, esterCH₃), 1.90-2.18 (m, 2H, gluCH₂), 2.43 (t, J=7Hz, 2H, gluCH₂), 2.44 (s, 3H, C³—CH₃), 4.05 (q, J=7 Hz, 2H, esterCH₂),4.10 (q, J=6 Hz, 2H, esterCH₂), 4.36-4.46 (m, 1H, gluCH), 5.43 (s, 2H,CH₂O), 7.17 (d, J=9 Hz, 2H, Ar), 7.65 (d, J=9 Hz, 1H, Ar), 7.74 (dd,J=8, 2 Hz, 1H, Ar), 7.88 (d, J=9 Hz, 2H, Ar), 8.08 (d, J=8 Hz, 1H, Ar),8.26 (d, J=9 Hz, 1H, Ar), 8.58 (d, J=7 Hz, 1H, gluNH), 9.94 (s, 1H, Ar),12.59 (s, 1H, N²H). Anal. Calculated for C₃₀H₃₁N₃O₇.1/4H₂O: C, 65.50; H,5.77; N, 7.64. Found: C, 65.54; H, 5.77; N, 7.61.

E.N-(4-((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoyl)-L-glutamicacid

DiethylN-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoyl)-L-glutamate(0.18 g, 0.33 mmol) was suspended in ethanol (2 ml) and 0.25 N NaOH (8ml) and stirred 1.5 hours at room temperature with intermittent periodsof sonication. Additional ethanol (4 ml) and warming were required toobtain a homogeneous solution. The solution was stirred 3 hours at roomtemperature and then adjusted to pH 3 with 1 N HCl. The resultingsuspension was filtered, and the white solid washed with water and driedunder high vacuum to giveN-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoyl)-L-glutamicacid (0.158 g). ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.87-2.16 (m, 2H, gluCH₂),2.35 (t, J=7 Hz, 2H, gluCH₂), 2.44 (s, 3H, CH₃), 4.33-4.43 (m, 1H,gluCH), 5.43 (s, 2H, CH₂O), 7.16 (d, J=9 Hz, 2H, Ar), 7.64 (d, J=9 Hz,1H, Ar), 7.74 (dd, J=8, 2 Hz, 1H, Ar), 7.88 (d, J=9 Hz, 2H, Ar), 8.08(d, J=8 Hz, 1H, Ar), 8.26 (d, J=9 Hz, 1H, Ar), 8.47 (d, J=8 Hz, 1H,gluNH), 9.94 (s, 1H, Ar), 12.36 (br s, 2H, CO₂H's), 12.59 (s, 1H, N²H).Anal. Calculated for C₂₆H₂₃N₃O₇.1/4H₂O: C, 63.22; H, 4.79; N, 8.51.Found: C, 63.23; H, 4.80; N, 8.48.

EXAMPLE 37N-(4-(((3-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamicacid

A. DiethylN-(4-(((1,2-dihydro-1-oxo-3-pivalamidobenzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamate

To a hot solution ofN-(1,2-dihydro-9-methyl-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.94 g,3.0 mmol) in benzene (250 ml) under nitrogen were addedN-bromosuccinimide (0.57 g, 3.2 mmol) (Kodak) and2,2′-azobisisobutyronitrile (AIBN) (35 mg, 0.21 mmol) (Kodak). Thesolution was stirred at reflux for 1.5 hours and then concentrated invacuo to give crudeN-(9-bromomethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide.The pivalamide and N-(4-aminobenzoyl)-L-glutamic acid diethyl ester (2.5g, 7.8 mmol) (Aldrich) in DMF (10 ml) were stirred under nitrogen at105-110° C. for 5 minutes and then allowed to cool. Triethylamine (0.5ml, 3.6 mmol) was added and the solution was concentrated under highvacuum. The residue was purified by chromatography on silica gel (130 g)eluting with ethyl acetate:methylene chloride (1:19→2:3), followed byrecrystallization of the solid from ethanol/diethyl ether. This wasfiltered and dried under high vacuum to give diethylN-(4-(((1,2-dihydro-1-oxo-3-pivalamido-benzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamate(0.32 g) as a white solid. The filtrate was concentrated and the residuepurified by chromatography and crystallization to give an additional0.243 g. ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H, esterCH₃),1.16 (t, J=7 Hz, 3H, esterCH₃), 1.28 (s, 9H, t-butyl), 1.87-2.13 (m, 2H,gluCH₂), 2.39 (t, J=7 Hz, 2H, gluCH₂), 4.03 (q, J=7 Hz, 2H, esterCH₂),4.07 (q, J=7 Hz, 2H, esterCH₂), 4.30-4.40 (m, 1H, gluCH), 4.57 (d, J=6Hz, 2H, C⁹—CH₂), 6.63 (d, J=9 Hz, 2H, Ar), 7.04 (t, J=6 Hz, 1H, ArNH),7.53 (d, J=9 Hz, 1H, Ar), 7.61 (dd, J=8, 2 Hz, 1H, Ar), 7.62 (d, J=9 Hz,2H, Ar), 7.99 (d, J=8 Hz, 1H, Ar), 8.21 (d, J=8 Hz, 1H, gluNH), 8.22 (d,J=9 Hz, 1H, Ar), 9.75 (s, 1H, Ar), 11.25 (s, 1H, N²H), 12.30 (br s, 1H,NH). Mass spectrum (CI-CH₄) 630 (M+1, 6.5%), 243 (100%). Anal.Calculated for C₃₄H₃₉N₅O₇: C, 64.85; H, 6.24; N, 11.12. Found: C, 64.74;H, 6.25; N, 11.10.

B.N-(4-(((3-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamicacid

A solution of diethylN-(4-(((1,2-dihydro-1-oxo-3-pivalamidobenzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamate(0.31 g, 0.49 mmol) in methanol (15 ml) and 1 N NaOH (5 ml) was stirredunder nitrogen at reflux for 1.5 hours and then allowed to cool. Thesolution was adjusted to pH 3 with 1 N-HCl under nitrogen and theresulting precipitate was filtered under nitrogen, washed with water,and dried under high vacuum to giveN-(4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamicacid (0.22 g) as a white solid. ¹H NMR (DMSO-d₆, 300 MHz δ: 1.82-2.12(m, 2H, gluCH₂), 2.31 (t, J=7 Hz, 2H, gluCH₂), 4.27-4.38 (m, 1H, gluCH),4.50 (d, J=6 Hz, 2H, C⁹—CH 2), 6.55 (br s, 2H, NH₂), 6.62 (d, J=9 Hz,2H, Ar), 6.96 (t, J=6 Hz, 1H, ArNH), 7.26 (d, J=9 Hz, 1H, Ar), 7.44 (dd,J=8, 2 Hz, 1H, Ar), 7.63 (d, J=9 Hz, 2H, Ar), 7.84 (d, J=8 Hz, 1H, Ar),7.99 (d, J=9 Hz, 1H, Ar), 8.09 (d, J=8 Hz, 1H, gluNH), 9.67 (s, 1H, Ar),11.14 (br s, 1H, N²H), 12.32 (br s, 2H, CO₂H's). Anal. Calculated forC₂₅H₂₃N₅O₆H₂O: C, 59.17; H, 4.97; N, 13.80. Found: C, 59.31; H, 4.90; N,13.72.

EXAMPLE 383-Amino-9-((4-fluoroanilino)methyl)benzo[f]quinazolin-1(2H)-one

A. N-(9-Bromomethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamideN-(9-Methyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (6.58 g,0.02 mole) was dissolved in refluxing benzene (1650 ml). The reactionwas removed from heat and N-bromosuccinimide (4.54 g, 0.026 mmole,Kodak) added. The solution was heated under reflux for 1.5 hours.Benzene was removed in vacuo and the residue dried under high vacuum togive the bromomethyl derivative. ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.29 (s,9H, t-butyl); 4.94 (s, 2H, CH₂Br); 7.58 (d, J=9 Hz, 1H, Ar); 7.67 (dd,J=8, 2 Hz, Ar); 8.03 (d, J=8 Hz, 1H, Ar); 8.24 (d, J=9 Hz, 1H, Ar); 9.80(s, 1H, Ar).

B.N-(9-((4-Fluoroanilino)methyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

N-(9-Bromomethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide(0.97 g, 2.5 mmole) and 4-fluoroaniline (0.56 g, 5 mmole) (Aldrich) weredissolved in dimethylformamide (15 ml). The reaction was stirred for 30minutes at 100° C., sodium bicarbonate (0.42 g, 5 mmole) added and thesuspension stirred for a further 30 minutes. The dimethylformamide wasremoved in vacuo, the residue washed with methylene chloride andfiltered. The filtrate was evaporated, and the residue was subjected tochromatography on a Waters Prep 500 instrument (silica cartridge,elution with ethyl acetate/methylene chloride (1:19)). Fractionscontaining product were concentrated in vacuo, the residue dissolved ina minimum amount of ethyl acetate, and the solution diluted with hexaneuntil precipitate formed. The solid was collected by filtration anddried under high vacuum to give the title compound as a beige solid(0.305 g, 29%). ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.25 (s, 9H, t-butyl); 4.42(d, J=6 Hz, 2H, CH₂); 6.33 (t, J=6 Hz, 1H, NH); 6.53-6.60 (m, 2H, Ar);6.85 (t, J=8 Hz, 2H, Ar); 7.50 (d, J=10 Hz, 1H, Ar); 7.60 (dd, J=8, 2Hz, 1H, Ar); 7.96 (d, J=8 Hz, 1H, Ar); 8.19 (d, J=8 Hz, 1H, Ar); 9.72(s, 1H, Ar); 11.23 (s, 1H, NH); 12.28 (s, 1H, NH).

C. 3-Amino-9-((4-fluoroanilino)methyl)benzo[f]quinazolin-1(2H)-one

A mixture of methanol (8.75 ml) and 0.5 N-sodium hydroxide (5.8 ml) washeated under reflux under nitrogen for 15 minutes.N-(9-((4-Fluoroanilino)methyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide(0.305 g, 0.73 mole) was added and the solution heated under reflux for2 hours. The reaction mixture was cooled to room temperature andadjusted to pH 7 with N-hydrochloric acid. The white solid was collectedand washed with water, then suspended in 100 ml of boiling ethanol. Thecooled solution was filtered and the collected solid dried under highvacuum to give3-amino-9-((4-fluoroanilino)methyl)benzo[f]quinazolin-1(2H)-one. (0.161g, 66%). Mp>230° C. ¹H NMR (DMSO-d₆, 200 MHz) δ: 4.38 (s, 2H, CH₂); 6.25(br s, 1H, NH); 6.52-6.59 (m, 2H, Ar); 6.68 (br s, 2H, NH₂); 6.85 (t,J=9 Hz, 2H, Ar); 7.25 (d, J=9 Hz, 1H, Ar); 7.45 (d, J=9 Hz, 1H, Ar);7.83 (d, J=8 Hz, 1H, Ar); 8.00 (d, J=9 Hz, 1H, Ar); 9.62 (s, 1H, Ar);11.35 (br s, 1H, NH). Anal Calculated for C₁₉H₁₅FN₄O.17/50H₂O: C, 67.03;H, 4.64; N, 16.46. Found: C, 66.94; H, 4.51; N, 16.44.

Similarly the following compounds were prepared by reaction of theappropriate aromatic amine with the foregoing(benzoquinazoline-3-yl)pivalamide.

3-Amino-9-((4-nitroanilino)methyl)benzo[f]quinazolin-1(2H)-one

(0.095 g, 95%). Mp>230° C. ¹H NMR (DMSO-d₆, 200 MHz) δ: 4.58 (d, J=6 Hz,2H, CH₂); 6.54 (s, 2H, NH₂); 6.69 (d, J=9 Hz, 2H, Ar); 7.26 (d, J=9 Hz,1H, Ar); 7.41 (d, J=8 Hz, 1H, Ar); 7.84 (d, J=8 Hz, 1H, Ar); 7.94-8.01(m, 4H, Ar & NH); 9.63 (s, 1H, Ar) 11.12 (s, 1H, NH). Anal Calculatedfor C₁₉H₁₅N₅O₃.1/4H₂O: C, 62.38; H, 4.27; N;19.14. Found: C, 62.44; H,4.28; N, 19.06.

3-Amino-9-((4-acetylanilino)methyl)benzo[f]quinazolin-1(2H)-one

(0.245 g, 98%). ¹H NMR (DMSO-d₆, 300 MHz) δ: 2.37 (s, 3H, CH₃); 4.53 (d,J=6 Hz, CH₂); 6.56 (br s, 2H, NH₂); 6.64 (d, J=9 Hz, 2H, Ar); 7.27 (d,J=9 Hz, 2H, Ar); 7.34 (t, J=6 Hz, 1H, NH); 7.43 (dd, J=8, 2 Hz, 1H, Ar);7.68 (d, J=9 Hz, 2H, Ar); 7.84 (d, J=8 Hz, 1H, Ar); 8.00 (d, J=9 Hz, 1H,Ar); 9.66 (s, 1H, Ar); 11.14 (br s, 1H, NH). Anal Calculated forC₂₁H₁₇N₄O₂.H₂O: C, 67.19; H, 5.10; N, 14.92. Found: C, 67.16; H, 5.18;N, 14.90.

3-Amino-9-((3-fluoranilino)methyl)benzo[f]quinazolin-1(2H)-one

(0.19 g, 95%). Mp>235° C. ¹H NMR (DMSO-d₆, 200 MHz) δ: 4.41 (d, J=6 Hz,2H, CH₂); 6.24-6.44 (m, 3H, Ar); 6.55 (s, 2H, NH₂); 6.68 (t, J=5 Hz, 1H,NH); 7.01 (q, J=8 Hz, 1H, Ar); 7.25 (d, J=9 Hz, 1H, Ar); 7.43 (d, J=8Hz, 1H, Ar); 7.82 (d, J=8 Hz, 1H, Ar); 7.98 (d, J=9 Hz, 1H, Ar); 9.64(s,1H, Ar); 11.15 (br s, 1H, NH). Anal Calculated for C₁₉H₁₅FN₄O.3/4H₂O: C,65.60; H, 4.78; N, 16.11. Found: C, 65.52; H, 4.76; N, 16.08.

EXAMPLE 39N-(4-((3-Amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-7-yl)amino)benzoyl)-L-glutamicacid andN-(4-((3-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-7-yl)amino)benzoyl)-L-glutamicacid

A. N-(5,6,7,8-Tetrahydro-1-naphthyl)acetamide

Acetic anhydride (100 ml, 1.06 mole) was added rapidly to neat1-amino-5,6,7,8-tetrahydronaphthalene (25 g, 0.17 mole) (Aldrich) withstirring. The mixture quickly solidified and was allowed to standovernight. The broken mass was suspended in hexane (200 ml), filtered,then resuspended in methylene chloride (150 ml). After stirring 10minutes, the suspension was diluted with an equal volume of hexane,filtered, and the solid dried at 95° C. under reduced pressure to giveN-(5,6,7,8-tetrahydro-1-naphthyl)acetamide (23 g). ¹H NMR (CDCl₃, 200MHz) δ: 1.68-1.90 (m, 4H, CH₂'s), 2.20 (s, 3H, CH₃), 2.52-2.68 (m, 2H,ArCH₂), 2.70-2.84 (m, 2H, ArCH₂), 3.94 (br s, 1H, NH), 6.92 (d, J=8 Hz,1H, Ar), 7.10 (t, J=8 Hz, 1H, Ar), 7.53 (d, J=8 Hz, 1H, Ar). Anal.Calculated for C₁₂H₁₅NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 76.13; H,8.04; N, 7.40.

B. N-(4-Cyanophenyl)-N-(5,6,7,8-tetrahydro-1-naphthyl)acetamide

To a solution of N-(5,6,7,8-tetrahydro-1-naphthyl)acetamide (23 g, 0.12mole) in DMF (120 ml) was added 80% NaH (3.9 g, 0.13 mole) portion wiseover a 45 minute period and the mixture was stirred until hydrogenevolution had ceased as monitored by bubbler. 4-Fluorobenzonitrile (18g, 0.15 mole) (Aldrich) was added, and the solution stirred at 90° C.under nitrogen for 3 hours. The reaction mixture was acidified withacetic acid, diluted with water (500 ml), and extracted with methylenechloride (2×500 ml). The combined extracts were washed with water (100ml), dried (MgSO₄), and concentrated in vacuo. The residue in a smallvolume of methylene chloride was applied to a silica gel column andeluted with ethyl acetate:hexane (1:3) to giveN-(4-cyanophenyl)-N-(5,6,7,8-tetrahydro-1-naphthyl)acetamide (13.4 g).¹H NMR (CDCl₃, 200 MHz) δ: 1.55-1.85 (m, 4H, CH₂'s), 1.96 (s, 3H, CH₃),2.10-2.32 (m, 1H, ArCH₂), 2.47-2.66 (m, 1H, ArCH₂), 2.76-2.88 (m, 2H,ArCH₂), 7.06 (dd, J=7, 2 Hz, 1H, Ar), 7.13-7.29 (m, 2H, Ar), 7.40 (d,J=9 Hz, 2H, Ar), 7.55 (d, J=9 Hz, 2H, Ar). Anal. Calculated forC₁₉H₁₈N₂O: C, 77.16; H, 6.34; N, 9.47. Found: C, 77.08; H, 6.12; N,9.51.

C.N-(4-Cyanophenyl)-N-(5,6,7,8-tetrahydro-1-naphthyl)-2,2,2-trifluoroacetamide

A solution ofN-(4-cyanophenyl)-N-(5,6,7,8-tetrahydro-1-naphthyl)acetamide (13.4 g,45.3 mmol) in ethanol (100 ml) and 5N NaOH (11 ml) was stirred at refluxfor 25 minutes, then acidified with acetic acid and concentrated invacuo. The residue was taken up in diethyl ether (200 ml), washed withwater (30 ml), and dried (K₂CO₃). Trifluoroacetic anhydride (25 ml, 0.18mole) (Aldrich) was added cautiously and the solution stirred overnightat room temperature. The reaction mixture was concentrated in vacuo to avolume of 100 ml, additional trifluoroacetic anhydride (20 ml, 0.14mole) added, stirred for 2 hours, then concentrated in vacuo. Theresidue was purified by chromatography on silica gel eluting withdiethyl ether:hexane (1:2); the product crystallized upon concentrationof the solution. The solid was filtered, washed with hexane, and driedat 95° C. under reduced pressure to giveN-(4-cyanophenyl)-N-(5,6,7,8-tetrahydro-1-naphthyl)-2,2,2-trifluoroacetamide (10.7 g). ¹H NMR (CDCl₃, 200 MHz) δ: 1.60-1.85 (m, 4H, CH₂'s),2.01-2.21 (m, 1H, ArCH₂), 2.55-2.73 (m, 1H, ArCH₂), 2.73-2.86 (m, 2H,ArCH₂), 7.10-7.29 (m, 3H, Ar), 7.39 (d, J=9 Hz, 2H, Ar), 7.64 (d, J=9Hz, 2H, Ar). Anal. Calculated for C₁₉H₅F₃N₂O: C, 66.27; H, 4.39; N,8.14. Found: C, 66.35; H, 4.40; N, 8.07.

D. N-(4-Cyanophenyl)-N-(7,8-dihydro-1-naphthyl)-2,2,2-trifluoroacetamide

A solution ofN-(4-cyanophenyl)-N-(5,6,7,8-tetrahydro-1-naphthyl)-2,2,2-trifluoroacetamide (10.7 g, 31.1 mmol), N-bromosuccinimide (6.6 g, 37 mmol), andAIBN (200 mg, 1.2 mmol) in CCl₄ (300 ml) was stirred at reflux undernitrogen for 1 hour. After coupling the solution was filtered,concentrated in vacuo to a volume of 25 ml, and applied to a column ofsilica gel. Elution with ethyl acetate:hexane (1:10) gave a mixture ofbenzylic bromides (10.7 g). A solution of the bromides and Li₂CO₃ (5.0g, 68 mmol) in DMF (50 ml) was stirred at 110-120° C. under nitrogen for3 hours and then overnight at room temperature. The solution wasconcentrated in vacuo and the residue taken up in methylene chloride(150 ml) and washed with water (50 ml). The aqueous phase was separated,extracted with more methylene chloride (100 ml), and the combinedorganic solutions were then washed with a small volume of water, dried(K₂CO₃) and concentrated in vacuo. The residue was purified bychromatography on silica gel eluting with ethyl acetate:hexane (1:13) togiveN-(4-cyanophenyl)-N-(7,8-dihydro-1-naphthyl)-2,2,2-trifluoroacetamideand the corresponding 5,6-dihydro isomer in a 3:1 ratio as determined byNMR (4.3 g). ¹H NMR (DMSO-d₆, 200 MHz) δ: 2.10-2.46 (m, 3H, CH₂),2.63-2.89 (m, 1H, CH₂), 6.03-6.22 (m, 1H, CH), 6.41 (dt, J=10,2 Hz,0.25H, CH), 6.48 (dt, J=10,2 Hz, 0.75H, CH), 7.08-7.33 (m, 3H, Ar), 7.41(d, J=9 Hz, 2H, Ar), 7.64 (d, J=9 Hz, 2H, Ar). Anal. Calculated forC₁₉H₁₃F₃N₂O: C, 66.67; H, 3.83; N, 8.18. Found: C, 66.55; H, 3.86; N,8.10.

E.N-(4-Cyanophenyl)-2,2,2-trifluoro-N-(1b,2,3,7a-tetrahydronaphth[1,2-b]oxiren-4-yl)acetamide

A solution of a 3:1 mixture ofN-(4-cyanophenyl)-N-(7,8-dihydro-1-naphthyl)-2,2,2-trifluoro acetamideand the corresponding 5,6-dihydro isomer (4.3 g, 13 mmol) andm-chloroperoxybenzoic acid (80-85%, 4.0 g, 19 mmol) (Aldrich) inmethylene chloride (60 ml) was stirred for 50 minutes at roomtemperature. The solution was diluted with methylene chloride (100 ml),washed with saturated NaHCO₃ solution (2×30 ml), dried (K₂CO₃), andconcentrated in vacuo. The epoxide isomers were separated bychromatography on silica gel eluting with diethyl ether:hexane (7:13 to9:11) and recrystallization of the enriched isomer from diethylether:hexane. The mother liqour was combined with some mixed fractionsfrom the chromatography and purified by repeating the procedure. Thecombined solid was dried under high vacuum to giveN-(4-cyanophenyl)-2,2,2-trifluoro-N-(1a,2,3,7b-tetrahydronaphth[1,2-b]oxiren-4-yl)acetamide(2.8 g). ¹H NMR (CDCl₃, 200 MHz) δ: 1.69 (dt, J=14,5 Hz, 1H, CH₂),2.03-2.25 (m, 1H, CH₂), 2.31-2.69 (m, 2H, CH₂), 3.70-3.78 (m, 1H, OCH),3.90 (d, J=4 Hz, 1H, OCH), 7.29-7.42 (m, 4H, Ar), 7.50-7.60 (m, 1H, Ar),7.63 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C₁₉H₁₃F₃N₂O₂: C, 63.69;H, 3.66; N, 7.82. Found: C, 63.70; H, 3.66; N, 7.76.

F.N-(4-Cyanophenyl)-2,2,2-trifluoro-N-(5,6,7,8-tetrahydro-6-oxo-1-naphthyl)acetamide

A solution ofN-(4-cyanophenyl)-2,2,2-trifluoro-N-(1a,2,3,7b-tetrahydronaphth[1,2-b]oxiren-4-yl)acetamide(2.8 g, 7.8 mmol) in diethyl ether (80 ml) was treated with BF₃.Et₂O(2.0 ml, 16 mmol) and the resulting suspension was stirred at roomtemperature. The suspension was diluted with methylene chloride after 1and 3 hours (80 and 40 ml) and additional BF₃.Et₂O (2×1.0 ml, 16 mmol)was added at 2 and 4 hour intervals. The reaction mixture was stirredovernight, then saturated NaHCO₃ solution (70 ml) slowly added. Theaqueous phase was separated and extracted with methylene chloride (40ml). The organic solutions were dried (K₂CO₃), concentrated in vacuo,and the residue purified by chromatography on silica gel with diethylether:hexane (2:3 to 1:1) to giveN-(4-cyanophenyl)-2,2,2-trifluoro-N-(5,6,7,8-tetrahydro-6-oxo-1-naphthyl)acetamide(1.17 g). ¹H NMR (CDCl₃, 200 MHz) δ: 2.44 (t, J=7 Hz, 2H, CH₂), 2.69(dt, J=16, 7 Hz, 1H, CH₂), 3.03 (dt, J=16, 6 Hz, 1H, CH₂), 3.63(strongly coupled AB pair, 2H, C⁵H₂), 7.25-7.45 (m, 5H, Ar), 7.67 (d,J=9 Hz, 2H, Ar). Anal. Calculated for C₁₉H₃F₃N₂O₂: C, 63.69; H, 3.66; N,7.82. Found: C, 63.75; H, 3.72; H, 7.74.

G. Methyl 5-(N-(4-cyanophenyl)-22.2-trifluoroacetamido)-3,4-dihydro-2-hydroxy-1-naphthalene carboxylate

A solution ofN-(4-cyanophenyl)-2,2,2-trifluoro-N-(5,6,7,8-tetrahydro-6-oxo-1-naphthyl)acetamide(1.17 g, 3.27 mmol) in THF (15 ml) was added dropwise over a 15 minuteperiod to a stirred suspension of 80% NaH (0.30 g, 10 mmol) (Aldrich) inmethyl cyanoformate (1.5 ml, 19 mmol) (Aldrich) and THF (15 ml) undernitrogen. The reaction mixture was stirred 30 minutes at roomtemperature then quenched with acetic acid (0.7 ml, 12 mmol). Thesolution was concentrated in vacuo onto silica gel (3 g) and theabsorbed material purified by chromatography on silica gel (30 g)eluting with ether:hexane (1:4 to 1:3) to give methyl5-(N-(4-cyanophenyl)-2,2,2-trifluoroacetamido)-3,4-dihydro-2-hydroxy-naphthalenecarboxylate (0.64 g). ¹H NMR (CDCl₃, 200 MHz) δ: 2.5-2.9 (m, 4H,CH₂CH₂), 3.93 (s, 3H, CH₃), 7.10 (d, J=8 Hz, 1H, Ar), 7.32 (t, J=8 Hz,1H, Ar), 7.39 (d, J=9 Hz, 2H, Ar), 7.64 (d, J=9 Hz, 2H, Ar), 7.82 (d,J=8 Hz, 1H, Ar), 13.35 (s, 1H, OH). Anal. Calculated for C₂₁H₁₅F₃N₂O₄:C, 60.58; H, 3.63; N, 6.73. Found: C, 60.66; H, 3.66; N, 6.68.

H.N-(7-(4-Cyanoanilino)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

To a solution of sodium ethoxide, prepared by reacting sodium (0.28 g,12 mmol) with ethanol (6 ml), was added guanidine hydrochloride (1.2 g,12 mmol) and the mixture was briefly stirred at reflux. A solution ofmethyl5-(N-(4-cyanophenyl)-2,2,2-trifluoroacetamido)-3,4-dihydro-2-hydroxy-1-naphthalenecarboxylate (0.63 g, 1.5 mmol) in ethanol (6 ml) was added and thereaction mixture was stirred at reflux under nitrogen for 18 hours. Thesolution was diluted with water (50 ml), neutralized with acetic acid,and the resulting precipitate filtered and dried at 110° C. underreduced pressure. A solution of the solid in pivalic anhydride (10 ml)was refluxed for ^(˜)5 minutes and then concentrated under high vacuum.The residue was eluted on silica gel (30 g) with ethyl acetate:methylenechloride (1:9) and the resulting solid recrystallized from diethylether, the slurry diluted with hexane, filtered, and the solid dried at100° C. under reduced pressure to giveN-(7-(4-cyanoanilino)-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide(0.48 g). ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.23 (s, 9H, t-butyl), 2.67 (s,4H, ArCH₂'s), 6.68 (d, J=9 Hz, 2H, Ar), 7.10 (d, J=8 Hz, 1H, Ar), 7.26(t, J=8 Hz, 1H, Ar), 7.50 (d, J=9 Hz, 2H, Ar), 8.38 (d, J=8 Hz, 1H, Ar),8.53 (s, 1H, C⁷—NH), 11.28 (br s, 1H, N²H), 12.16 (br s, 1H, C³—NH). Asolution of the pivalamide (0.15 g) and 10% palladium on carbon (70 mg)in diglyme (5 ml) was stirred at reflux under nitrogen for 10 hours.Pivalic anhydride (2×0.5 ml, 4.9 mmol) was added at 5 and 9 hours. Thesolution was diluted with diglyme (15 ml), filtered hot through celite,and concentrated under high vacuum. The residue was purified bychromatography on silica gel (15 g) eluting with ethyl acetate:methylenechloride (1:9) and then recrystallization from methanol. The solid wasfiltered and dried at 90° C. under reduced pressure to giveN-(7-(4-cyanoanilino)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide(86 mg). ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.26 (s, 9H, t-butyl), 6.85 (d,J=9 Hz, 2H, Ar), 7.49-7.60 (m, 4H, Ar), 7.72 (t, J=8 Hz, 1H, Ar); 8.29(d, J=9 Hz, 1H, Ar); 9.07 (s, 1H, C⁷—NH), 9.61 (d, J=9 Hz, 1H, Ar),11.25 (br s, 1H, N H), 12.32 (br s, 1H, C³—NH). Mass spectrum (CI-CH₄)412 (M+1, 100%). Anal. Calculated for C₂₄H₂₁N₅O₂.17/100H₂O: C, 69.54; H,5.19; N, 16.89. Found: C, 69.56; H, 5.23; N, 16.88.

I. DiethylN-(4-((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-7-yl)amino)benzoyl)-L-glutamate

A suspension ofN-(7-(4-cyanoanilino)-1,2-dihydro-1-oxobenzo[f]-quinazolin-3-yl)pivalamide(82 mg, 0.20 mmol) in ethanol (1 ml) and 1N NaOH (4 ml) was stirredunder nitrogen at reflux overnight. The solution was allowed to cool,acidified to pH 3 with concentrated HCl, the resulting suspensionstirred for 30 minutes,then filtered. The solid was washed with waterand dried at 120° C. under reduced pressure to give4-((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-7-yl)amino)benzoic acid.¹H NMR (DMSO-d₆, 200 MHz) δ: 6.85 (d, J=9 Hz, 2H, Ar), 7.30 (br s, 2H,NH₂), 7.39 (d, J=9 Hz, 1H Ar), 7.43 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8Hz, 1H, Ar), 7.73 (d, J=9 Hz, 2H, Ar), 8.28 (d, J=9 Hz, 1H, Ar), 8.85(s, 1H, C⁷—NH), 9.44 (d, J=9 Hz, 1H, Ar), 11.5-12.9 (2H, CO₂H and N²H).A solution of the foregoing benzoic acid, L-glutamic acid diethyl esterhydrochloride (80 mg, 0.33 mmol) (Aldrich),benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate(90 mg, 0.20 mmol) (Richelieu Biotechnologies), and triethylamine (90 l,0.64 mmol) in DMF (6 ml) was stirred at room temperature for 1 hour,then concentrated under high vacuum. The residue was purified bychromatography on silica gel (10-15 g) three times eluting withmethanol/methylene chloride. Water (^(˜)5 ml) was added to a solution ofthe solid in ethanol, the ethanol removed under vacuum, and the solidfiltered, washed with water, and dried under high vacuum to give diethylN-(4-((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-7-yl)amino)benzoyl)-L-glutamate(35 mg). ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.14 (t, J=7 Hz, 3H, CH₃), 1.16(t, J=7 Hz, 3H, CH₃), 1.85-2.15 (m, 2H, gluCH₂), 2.40 (t, J=7 Hz, 2H,gluCH₂), 4.03 (q, J=7 Hz, 2H, esterCH₂), 4.08 (q, J=7 Hz, 2H, esterCH₂),4.30-4.45 (m, 1H, gluCH), 6.63 (br s, 2H, NH₂), 6.85 (d, J=9 Hz, 2H,Ar), 7.29 (d, J=9 Hz, 1H, Ar), 7.35 (d, J=8 Hz, 1H, Ar), 7.56 (t, J=8Hz, 1H, Ar), 7.71 (d, J=9 Hz, 2H, Ar), 8.18 (d, J=9 Hz, 1H, Ar), 8.36(d, J=7 Hz, 1H, gluNH), 8.64 (s, 1H, C⁷—NH), 9.45 (d, J=9 Hz, 1H, Ar),11.22 (br s, 1H, N²H). Mass spectrum (CI-CH₄): 532 (M+1, 62.5%), Anal.Calculated for C₂₈H₂₉N₅O₆.H₂O: C, 61.19; H, 5.69; N, 12.74. Found: C,61.20; H, 5.44; N, 12.68.

J. DiethylN-(4-((3-amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-7-yl)amino)benzoyl)-L-glutamate

(0.061 g, 46%) was similarly prepared fromN-(7-(4-cyanoanilino)-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide(0.10 g, 0.24 mmol). ¹H NMR (DMSO-d₆, 300 MHz) δ: 1.17 (t, J=7 Hz, 3H,CH₃), 1.19 (t, J=7 Hz, 3H, CH₃), 1.90-2.16 (m, 2H, gluCH₂), 2.42 (t, J=7Hz, 2H, gluCH₂), 2.45-2.55 (m, 2H, ArCH₂), 2.58-2.67 (m, 2H, ArCH₂),4.05 (q, J=7 Hz, 2H, esterCH₂), 4.09 (q, J=7 Hz, 2H, esterCH₂),4.34-4.44 (m, 1H, gluCH), 6.67 (d, J=9 Hz, 2H, Ar), 6.7 (br s, 2H, NH₂),6.99 (d, J=8 Hz, 1H, Ar), 7.16 (t, J=8 Hz, 1H, Ar), 7.70 (d, J=9 Hz, 2H,Ar), 8.10 (S, 1H, ArNH), 8.30 (d, J=8 Hz, 1H, Ar), 8.33 (d, J=8 Hz, 1H,gluNH), 10.92 (S, 1H, N²H). Mass spectrum (CI-CH₄): 534 (M+1, 100%).Anal. Calculated for C₂₈H₃₁N₅O₆.17/20H₂O: C, 61.27; H, 6.00; N, 12.76.Found: C, 61.21; H, 5.94; N, 12.70.

K.N-(4-((3-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-7-yl)amino)benzoyl)-L-glutamicacid

A solution of diethylN-(4-((3-amino-1,2-dihydro-1-oxobenzo[f]-quinazolin-7-yl)amino)benzoyl)-L-gluamate(31 mg, 0.056 mmol) in ethanol (1 ml) and 0.25 N NaOH (4 ml) was stirredunder nitrogen at room temperature for 3 hours. The solution was thenacidified to pH 3 with 1N hydrochloric acid and the resulting suspensionallowed to stir for 15 minutes. The solid was filtered, washed withwater, and dried under high vacuum to giveN-(4-((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-7-yl)amino)benzoyl)-L-glutamicacid (27 mg). ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.79-2.16 (m, 2H, gluCH₂),2.32 (t, J=7 Hz, 2H, gluCH₂), 4.27-4.41 (m, 1H, gluCH), 6.55 (br s, 2H,NH₂), 6.85 (d, J=9 Hz, 2H, Ar), 7.27 (d, J=9 Hz, 1H, Ar), 7.34 (d, J=7Hz, 1H, Ar), 7.55 (t, J=8 Hz, 1H, Ar), 7.72 (d, J=9 Hz, 2H, Ar), 8.16(d, J=9 Hz, 1H, Ar), 8.24 (d, J=8 Hz, 1H, gluNH), 8.62 (s, 1H, C⁷—NH),9.45 (d, J=9 Hz, 1H, Ar), 11.13 (br s, 1H, N²H), 12.31 (br s, 2H,CO₂H's). Anal. Calculated for C₂₄H₂₁N₅O₆.5/4H₂O: C, 57.89; H, 4.76; N,14.06. Found: C, 57.93; H, 4.73; N, 13.99.

L.N-(4-((3-Amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-7-yl)amino)benzoyl)-L-glutamicacid

(27 mg, 52%) was similarly prepared from diethylN-(4-((3-amino-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-7-yl)amino)benzoyl)-L-glutamate(56 mg, 0.10 mmol). ¹H NMR (DMSO-d₆, 200 MHz) δ: 1.78-2.16 (m, 2H,gluCH₂), 2.32 (t, J=7 Hz, 2H, gluCH₂), 2.40-2.54 (m, 2H, ArCH₂),2.54-2.67 (m, 2H, ArCH₂), 4.27-4.43 (m, 1H, gluCH), 6.65 (overlapping brs, 2H, NH₂ and d, J=9 Hz, 2H, Ar), 6.97 (dd, J=8, 1 Hz, 1H, Ar), 7.14(t, J=8 Hz, 1H, Ar), 7.68 (d, J=9 Hz, 2H, Ar), 3.07 (s, 1H, ArNH), 8.19(d, J=8 Hz, 1H, gluNH), 8.27 (dd, J=8, 1 Hz, 1H, Ar), 10.90 (br s, 1H,N²H), 12.30 (br s, 2H, CO₂H's). Anal. Calculated for C₂₄H₂₃N₅O₆.8/5H₂O:C, 56.94; H, 5.22; N, 13.83. Found: C, 56.96; H, 5.21; N, 13.86.

EXAMPLE 40 3-Amino-9-chloro-5,6-dihydrobenzo[f]quinazolin-1(2H)-onehydrochloride

1,3-Diamino-9-chloro-5,6-dihydroquinazoline (4.0 g) (A. Rosowsky et al.,J. Heterocyclic Chem., 9, 263, (1972)) was heated under reflux with 6-MHCl (400 ml) for 2.5 hr. The solution was filtered to remove the1-amino-3-oxo-isomer of the title compound (0.6 g), and the filtrateheated for a further 1.5 hr. The product was collected by filtrationfrom the cooled reaction mixture, washed with water and dried undervacuum (0.508 g) ¹H NMR (DMSO-d₆, 250 MHz) δ: 2.82 (m, 4H, CH₂), 4.0 (vbr s, 1H), 7.26 (m, 2H, Ar), 8.27, br s, 2H, NH₂), 8.38 (s, 1H, Ar).Anal. Calculated for C₁₂H₁₀ClN₃O.HCl: C, 50.72; H, 3.90; N, 14.59.Found: C, 50.56; H, 4.04; N, 14.51.

Also prepared from the corresponding diamines (A. Rosowsky et al., J.Heterocyclic Chem., 9, 263, (1972)) by an essentially similar procedurewere 3-Amino-5,6-dihydro-8-methoxybenzo[f]quinazolin-1(2H)-onehydrochloride, (9.5% from diamine), ¹H NMR (DMSO-d₆, 250 MHz) δ: 2.77(m, 4H, CH₂), 3.76 (s, 3H, OCH₃), 6.81 (m, 1H), 8.27 (m, 2H), 8.10 (brs, 1H). Mass spectrum (EI): 243, (M⁺), 100%. Anal. Calculated forC₁₃H₁₃N₃O₂.HCl.11/25H₂O: C, 54.27; H, 5.21; N, 14.61. Found: C, 54.55;H, 5.53; N, 14.46.

3-Amino-5,6-dihydro-7-methoxybenzo[f]quinazolin-1(2H)-one hydrochloride,(24.7% from diamine), ¹H NMR (DMSO-d₆, 80 MHz) δ: 2.75 (m, 4H, CH₂),3.80 (s, 3H, OCH₃), 7.08 (m, 2H, Ar), 8.00 (m, 1H, Ar), 8.21 (br s, 1H,NH). Anal. Calculated for C₁₃H₁₃N₃O₂.HCl.4/5H₂O: C, 53.08; H, 5.35; N,14.29. Found: C, 52.99; H, 5.36; N, 14.32; and

3-Amino-5,6-dihydro-9-methoxybenzo[f]quinazolin-1(2H)-one hydrochloride,(15.6% from diamine), ¹H NMR (DMSO-d₆, 80 MHz) δ: 2.76 (m, 4H, CH₂),3.73 (s, 3H, OCH₃), 6.76 (dd, J=8, 2.5 Hz, 1H, Ar), 7.14(d, J=8 Hz, 1H,Ar), 8.00 (d, J=2.5 Hz, 1H, Ar), 8.19 (br s, 1H, NH). Anal. Calculatedfor C₁₃H₁₃N₃O2.HCl: C, 55-82; H, 5.04; N, 15.02. Found: C, 55.67; H,5.09; N, 15.03.

EXAMPLE 41 2,4-Diaminodibenzo[f,h]quinazoline

A solution of 9-aminophenanthrene (1.0 g, 5.2 mmol) (Aldrich) and sodiumdicyanamide (0.90 g, 10 mmol) in warm acetic acid (50 ml) was allowed tocool to room temperature and stirred for 1 hour. The solution wasdiluted with water (200 ml), adjusted to pH 6 with NH₄OH, and extractedwith methylene chloride (200 ml). The organic phase was dried (K₂CO₃),concentrated in vacuo, and the residue purified by chromatography onsilica gel eluting with ethyl acetate:methylene chloride (1:1) to givean uncyclized adduct (0.82 g). A solution of this solid in diglyme (20ml) was stirred at reflux under nitrogen for 1 hour and thenconcentrated in vacuo. The solid was suspended in methylene chloride,filtered, and then eluted on silica gel (15 g) with methanol:methylenechloride (1:9). Solid precipitated upon concentration in vacuo of eluentand was filtered and dried at 85° C. under reduced pressure to give2,4-diaminodibenzo[f,h]quinazoline (0.26 g). ¹H NMR (DMSO-d₆, 200 MHz)δ: 6.24 (brs, 2H, NH₂), 6.92 (brs, 2H, NH₂), 7.42-7.80 (m, 4H, Ar), 8.57(dd, J=8, 2 Hz, 1H, Ar), 8.67 (d, J=8 Hz, 2H, Ar), 8.94 (dd, J=8, 2 Hz,1H, Ar). Anal. Calculated for C₁₆H₁₂N₄.O.25H₂O: C, 72.57; H, 4.76; N,21.16. Found: C, 72.63; H, 4.69; N, 21.14.

2-Aminodibenzo[f,h]quinazolin-4(3H)-one

A suspension of 2,4-diaminodibenzo[f,h]quinazoline (0.20 g, 0.76 mmol)in 1 N HCl (150 ml) was stirred at reflux for 24 h, then neutralizedwith NH₄OH. The resulting solid was filtered, washed with water andmethanol, then suspended in warm methanol (50 ml) for 20 minutes,filtered and dried at 90° C. under reduced pressure. The solid wasnearly dissolved in ethanol (100 ml) and 1 N NaOH (^(˜)1.5 ml),filtered, and the filtrate neutralized with acetic acid to give aprecipitate which was filtered, washed with ethanol, and dried at 90° C.under reduced pressure. The solid was briefly heated to reflux inpivalic anhydride (4 ml), the solution concentrated in vacuo, and theresidue subjected to chromatography on silica gel, eluting withmethylene chloride containing a small precentage of ethyl acetate. Thepivalamide (not characterized) was hydrolyzed in a solution of methanol(9 ml) and 1 N NaOH (1 ml) at reflux for 1.5 hours. The solution wasneutralized with acetic acid, and the precipitate filtered, washed withmethanol and dried at 90° C. under reduced pressure to give2-aminodibenzo[f,h]quinazolin-4-(3H)-one as a beige solid (0.10 g). ¹HNMR (DMSO-d₆, 200 MHz) δ: 6.69 (br s, 2H, NH₂), 7.47-7.84 (m, 4H, Ar),8.66-8.80 (m, 2H, Ar), 8.96 (dd, J=8, 1 Hz, 1H, Ar), 9.75-9.83 (m, 1H,Ar), 11.26 (br s, 1H, NH). Mass spectrum (CI-CH₄) 262 (M+1, 100%). Anal.Calculated for C₁₆H₁₁N₃O: C, 73.55; H, 4.24; N, 16.08. Found: C, 73.52;H, 4.27; N, 16.03.

Biological Test Data

The procedures used for evaluation of compounds of the invention asantitumour agents are detailed below.

Thymidylate Synthase Inhibition

Human thymidylate synthase (TS) from a SV40-transformed human fibroblastcell was cloned in Escherichia coli (I. Dev and W. Dallas, personalcommunication) and the protein purified to homogeneity by affinitychromatography (Rode, W., Scanlon, K. J., Hynes, J. B., Bertino, J. R.,J. Biol. Chem., 254, 1979, 11538).

The enzymes were assayed, and extent of inhibition of the enzyme by thevarious compounds was determined by the tritium release assay of Roberts(Biochemistry, 5, 1966, 3546.) as modified by Dev et al. (J. Biol.Chem., 264, 1989, 19132).

Inhibition of the Growth of tumor cells was determined as describedpreviously (Patil, S. D., Jones, C., Nair, M. G., Galivan, J., Maley,F., Kisliuk, R. L., Gaumont, Y., Duch, D., and Ferone, R., J. Med.Chem., 32, 1989, 1284) and modified as indicated below.

Cells and Medium

SW480 and WiDr colon adenocarcinomas, MCF-7 breast adenocarcinoma, A427lung carcinoma and MOLT-4 T-cell leukemia were used for the primaryscreening of compounds. WiDr and MOLT-4 cells were grown in RPMI 1640medium supplemented with 10 nM calcium leucovorin instead of folic acidas the folate source, 10% dialyzed fetal calf serum, penicillin andstreptomycin. MCF-7, A427 and SW480 were grown in the above mediumfurther supplemented with sodium pyruvate. (110 g/ml).

Cytotoxicity Assay

Cells are seeded into 96-well plates using a Perkin-Elmer Pro/pette.SW480 and A427 were seeded at 8,000 cells per well, MCF-7 at 10,000,Widr at 7500, and MOLT-4 at 12,500 cells per well, all in 150 l ofmedium. Prior to the addition of drugs, cultures were incubated for 24hrs at 37°. Compounds were added at 2×concentration in 150 l of mediumand each concentration was assayed in triplicate. If DMSO or ethanolwere used to solubilize compounds, appropriate controls were run if theconcentration exceeded 0.01%. Cultures were incubated for 72 hours (96hours for SW480 and MCF-7) in a 37° humidified incubator at 5% CO₂.Inhibition of cell growth was measured using the MTT dye reductionassay.

MTT Dye Reduction Assay

Cell dilutions for a standard curve were prepared from a 72 hourlog-phase culture. Serial dilutions were seeded in triplicate in 96-wellplates and incubated at 37 degrees for one hour. MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) wasdissolved in PBS at 5 mg/ml and sonicated for 30 seconds. Using thePerkin Elmer Pro/pette, 200 μl of medium was removed and 100 μl of MTTadded to the wells of the standard curve and test plates. Suspensioncultures were spun for 5 min at 1000 rpm before removing medium from thewells. Plates were incubated for 1 hour at 370 on a platform shaker.Following this incubation 100 ml of medium was removed from the wellsand 100 μl of DMSO added to each well. The plates were sonicated forapproximately 10 seconds to solubilize the precipitated formazan dye.The absorbance of each well was measured using a Titertek Multiscan MCmicrotiter plate reader at 570 nm with a reference wavelength of 750 nm.Data was collected using a Mariachi Seed-2 and stored and analyzed usingan IBM-AT and Lotus 1-2-3 software.

Table A.

Mammalian Thymidylate Synthase Enzyme Inhibition Data for Compounds ofthe present invention.

The following compounds had an I₅₀ of between 1 and 300 μM vs. mammalianenzymes.

3-Amino-9-chloro-5,6-dihydrobenzo(f)quinazolin-1(2H)-one *

3,9-Diamino-5,6-dihydrobenzo(f)quinazolin-1(2H)-one

3-Amino-9-ethoxy-5,6-dihydrobenzo(f)quinazolin-1(2H)-one *

3-Amino-N,N-diethyl-1,2,5,6-tetrahydro-1-oxobenzo(f)quinazoline-9-sulfonamide*

3-Amino-7-fluoro-5,6-dihydrobenzo(f)quinazolin-1(2H)-one *

3-Amino-5,6-dihydro-7-iodobenzo(f)quinazolin-1(2H)-one *

3,8-Diamino-5,6-dihydrobenzo(f)quinazolin-1(2H)-one

3-Amino-8-chloro-5,6-dihydrobenzo(f)quinazolin-1(2H)-one *

3-Amino-1,2,5,6-tetrahydro-1-oxobenzo(f)quinazoline-8-sulfonamide

3-Amino-5,6-dihydro-6,6-dimethylbenzo(f)quinazolin-1(2H)-one *

3-Amino-8-chloro-5,6-dihydro-6-methylbenzo(f)quinazolin-1(2H)-one *

3-Amino-9-bromo-5,6-dihydrobenzo(f)quinazolin-1(2H)-one

3-Amino-5,6-dihydro-9-hydroxybenzo(f)quinazolin-1(2H)-one *

3-Amino-5,6-dihydro-9-(methylthio)benzo(f)quinazolin-1(2H)-one *

3-Amino-5,6-dihydro-7-methylbenzo(f)quinazolin-1(2H)-one

3-Amino-5,6-dihydro-8-nitro(f)quinazolin-1(2H)-one

3-Amino-8-bromo-5,6-dihydrobenzo(f)quinazolin-1(2H)-one

3-Amino-8,9-dichloro-5,6-dihydrobenzo(f)quinazolin-1(2H)-one

3-Amino-9-bromo-5,6-dihydro-8-nitrobenzo(f)quinazolin-1(2H)-one *

3-Amino-9-fluoro-5,6-dihydrobenzo(f)quinazolin-1(2H)-one *

3-Amino-9-ethynyl-5,6-dihydrobenzo(f)quinazolin-1(2H)-one *

3-Amino-9-(ethylthio)-5,6-dihydrobenzo(f)quinazolin-1(2H)-one *

3-Amino-5,6-dihydro-6-methylbenzo(f)quinazolin-1(2H)-one

3-Amino-7-bromo-5,6-dihydrobenzo(f)quinazolin-1(2H)-one

3-Amino-8-fluoro-5,6-dihydrobenzo(f)quinazolin-1(2H)-one *

3-Amino-5,6-dihydro-7,9-dimethylbenzo(f)quinazolin-1(2H)-one

3,8-Diamino-9-bromo-5,6-dihydrobenzo(f)quinazolin-1(2H)-one *

3-Amino-8-bromo-N,N-diethyl-1,2,5,6-tetrahydro-1-oxobenzo(f)quinazoline-9-sulfonamide*

3-Amino-6-methylbenzo(f)quinazolin-1(2H)-one

3-Amino-7-bromobenzo(f)quinazolin-1(2H)-one *

3-Amino-9-methoxybenzo(f)quinazolin-1(2H)-one

3,8-Diaminobenzo(f)quinazolin-1(2H)-one *

3,10-diaminobenzo(f)quinazolin-1(2H)-one *

3-Amino-7,9-dimethylbenzo(f)quinazolin-1(2H)-one

3-Amino-8-bromo-9-nitrobenzo(f)quinazolin-1(2H)-one

3-Amino-8-fluoro-10-nitrobenzo(f)quinazolin-1(2H)-one *

3-Amino-8-bromo-7-nitrobenzo(f)quinazolin-1(2H)-one

3,10-Diamino-8-fluorobenzo(f)quinazolin-1(2H)-one

3-Amino-9-bromo-8-nitrobenzo(f)quinazolin-1(2H)-one

3,7-Diaminobenzo(f)quinazolin-1(2H)-one

3-Amino-8-fluorobenzo(f)quinazolin-1(2H)-one *

3-Amino-7-methylbenzo(f)quinazolin-1(2H)-one *

3-Amino-7-iodobenzo(f)quinazolin-1(2H)-one *

3-Amino-6-(methoxymethyl)benzo(f)quinazolin-1(2H)-one *

3,7-Diamino-8-bromobenzo(f)quinazolin-1(2H)-one

3-Amino-8-fluoro-7-nitrobenzo(f)quinazolin-1(2H)-one *

3-Amino-8-chloro-6-methylbenzo(f)quinazolin-1(2H)-one *

3,8,10-Triaminobenzo(f)quinazolin-1(2H)-one

3-Amino-8-bromo-N,N-diethyl-1,2-dihydro-1-oxobenzo(f)quinazoline-9-sulfonamide*

3-Amino-6-(hydroxymethyl)benzo(f)quinazolin-1(2H)-one

3-Amino-7-fluorobenzo(f)quinazolin-1(2H)-one *

3-Amino-8-chlorobenzo(f)quinazolin-1(2H)-one *

3-Amino-9-ethoxybenzo(f)quinazolin-1(2H)-one *

3-Amino-10-nitrobenzo(f)quinazolin-1(2H)-one *

2-Aminodibenzo(f,h)quinazolin-4(3H)-one *

3-Amino-8,10-dinitrobenzo(f)quinazolin-1(2H)-one *

3,8-Diamino-7,9-dibromobenzo(f)quinazolin-1(2H)-one

3-Amino-7-chlorobenzo(f)quinazolin-1(2H)-one

3-Amino-9-(ethylthio)benzo(f)quinazolin-1(2H)-one

3-Amino-N,N-dimethyl-1,2-dihydro-1-oxobenzo(f)quinazoline-9-sulfonamide

9-Chloro-5,6-dihydro-3-methylbenzo(f)quinazolin-1(2H)-one *

1,2,5,6-Tetrahydro-3-methyl-1-oxobenzo(f)quinazoline-9-sulfonylchloride*

1,2,5,6-Tetrahydro-3-methyl-1-oxobenzo(f)quinazoline-9-sulfonamide *

9-Bromo-5,6-dihydro-3-methylbenzo(f)quinazolin-1(2H)-one *

N,N-Diethyl-1,2,5,6-tetrahydro-3-methyl-1-oxobenzo(f)quinazoline-9-sulfonamide

5,6-Dihydro-7-iodo-3-methylbenzo(f)quinazolin-1(2H)-one *

9-Fluoro-5,6-dihydro-3-methylbenzo(f)quinazolin-1(2H)-one *

5,6-Dihydro-9-iodo-3-methylbenzo(f)quinazolin-1(2H)-one *

1,2,5,6-Tetrahydro-N,N, 3-trimethylbenzo(f)quinazoline-9-sulfonamide *

7-Chloro-5,6-dihydro-3-methylbenzo(f)quinazolin-1(2H)-one *

7-Chloro-3-methylbenzo(f)quinazolin-1(2H)-one *

9-Fluoro-3-methylbenzo(f)quinazolin-1(2H)-one *

7-Iodo-3-methylbenzo(f)quinazolin-1(2H)-one *

N-(4-(Methyl((1,2,5,6-tetrahydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)sulfonyl)amino)benzoyl)-L-glutamicacid *

N-(4-((3-Amino-1,2,5,6-tetrahydrobenzo(f)quinazolin-7-yl)amino)benzoyl)-L-glutamicacid *

N-(4-(((3-Amino-1,2,5,6-tetrahydro-1-oxobenzo(f)quinazolin-8-yl)sulfonyl)

(2-propynyl)amino)benzoyl)-L-glutamic acid*

N-(4-((3-Amino-9-bromo-1,2-dihydro-1-oxobenzo(f)quinazolin-8-yl)sulfonamido)benzoyl)-L-glutamicacid *

N-(4-((1,2,-Dihydro-3-methyl-1-oxobenzo(f)quinazolin-7-yl)sulfonamido)benzoyl)-L-glutamicacid *

3-Methyl-9-((4-nitroanilino)methyl)benzo)(f)quinazolin-1(2H)-one *

4-(((1,2-Dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methyl)amino)benzonitrile*

9-((2-Fluoroanilino)methyl)-3-methylbenzo(f)quinazolin-1(2H)-one *

9-((3,4-Difluoroanilino)methyl)-3-methylbenzo(f)quinazolin-1(2H)-one *

4-((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)oxy)benzonitrile *

N-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)carbonyl)amino)benzoyl)-1-glutamicacid *

N-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-8-yl)methyl)amino)benzoyl)-L-glutamicacid *

The following compounds have I₅₀ values of less than 1 μM

3-Amino-5,6-dihydro-9-methylbenzo(f)quinazolin-1(2H)-one *

3-Amino-9-chloro-5,6-dihydro-6-methylbenzo(f)quinazolin-1(2H)-one *

3-Amino-5,6-dihydro-9-iodobenzo(f)quinazolin-1(2H)-one *

3-Amino-9-chlorobenzo(f)quinazolin-1(2H)-one *

3-Amino-9-ethylbenzo(f)quinazolin-1(2H)-one *

3,10-Diamino-9-bromobenzo(f)quinazolin-1(2H)-one *

3-Amino-9-hydroxybenzo(f)quinazolin-1(2H)-one

3-Amino-9-((4-acetylanilino)methyl)benzo(f)quinazolin-1(2H)-one *

3-Amino-9-bromobenzo(f)quinazolin-1(2H)-one *

3-Amino-9-methylbenzo(f)quinazolin-1(2H)-one *

3,8-Diamino-9-bromobenzo(f)quinazolin-1(2H)-one

3-Amino-9-(methylthio)benzo(f)quinazolin-1(2H)-one

3,9-Diaminobenzo(f)quinazolin-1(2H)-one

3-Amino-9-fluorobenzo(f)quinazolin-1(2H)-one *

3-Amino-9-iodobenzo(f)quinazolin-1(2H)-one *

3-Amino-9-ethynylbenzo(f)quinazolin-1(2H)-one *

3-Amino-9-chloro-6-methylbenzo(f)quinazolin-1(2H)-one *

3-Amino-8,9-dichlorobenzo(f)quinazolin-1(2H)-one *

3-Amino-9-bromo-10-nitrobenzo(f)quinazolin-1(2H)-one *

4-(((3-Amino-1,2-dihydro-1-oxobenzo(f)quinazolin-9-yl)amino)sulfonyl)benzoicacid *

4′-Fluoro-1,2,5,6-tetrahydro-3-methyl-1-oxobenzo(f)quinazoline-9-sulfonanilide*

1,2,5,6-Tetrahydro-3-methyl-4′-nitro-1-oxobenzo(f)quinazoline-9-sulfonanilide*

4-((1,2,5,6-Tetrahydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)sulfonamido)benzamide*

4′-Acetyl-1,2,5,6-tetrahydro-3-methyl-1-oxobenzo(f)quinazoline-9-sulfonanilide*

9-Chloro-3-methylbenzo(f)quinazolin-1(2H)-one *

9-Bromo-3-methylbenzo(f)quinazolin-1(2H)-one *

9-Iodo-3-methylbenzo(f)quinazolin-1(2H)-one *

N-(4-((3-Amino-1,2,5,6-tetrahydro-1-oxobenzo(f)quinazolin-9-yl)-sulfonamido)benzoyl)-L-glutamicacid *

N-(4-(((3-Amino-8-bromo-1,2,5,6-tetrahydro-1-oxobenzo(f)quinazolin-9-yl)*

sulfonyl)amino)benzoyl)-L-glutamic acid *

N-(4-(((3-Amino-1,2,5,6-tetrahydro-1-oxobenzo(f)quinazolin-8-yl)sulfonyl)amino)benzoyl)-L-glutamicacid *

N-(4-((1,2,5,6-Tetrahydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamicacid *

N-(4-(((3-Amino-1,2-dihydro-1-oxobenzo(f)quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamicacid *

N-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamicacid *

(S)-2-(5-(((1,2-Dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)glutaricacid *

N-(4-((3-Amino-1,2-dihydro-1-oxobenzo(f)quinazolin-7-yl)amino)benzoyl)-L-glutamicacid *

N-(4-((1,2-Dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methyl)methylamino)benzoyl)-L-glutamicacid *

N-(4-((1,2-Dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methoxy)benzoyl)-L-glutamicacid *

N-(4-(((3-Amino-1,2-dihydro-1-oxobenzo(f)quinazolin-9-yl)amino)sulfonyl)benzoyl)-L-glutamicacid *

N-(4-((1,2-Dihydro-3-methyl-1-oxabenzo(f)quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamicacid *

N-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)-L-glutamicacid *

3-Methyl-9-(((1-oxo-5-indanyl)amino)methyl)benzo)[f]quinazolin-1(2H)-one*

4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)benzoicacid *

3-Methyl-9-(anilinomethyl)benzo(f)quinazolin-1(2H)-one *

9-((3-Chloroanilino)methyl)-3-methylbenzo(f)quinazolin-1(2H)-one *

(S)-2-(5-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)methylamino)-1-oxo-2-isoindolinyl)glutaricacid *

(RS)-2-(2-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)phenyl)-2-oxoethyl)glutaricacid *

(E)-N-(4-(2(1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)vinyl)benzoyl)-L-glutamicacid *

N-(4-(2-(1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)ethyl)benzoyl)-L-glutamicacid *

4-(4-(((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)phenyl)-4-oxobutyricacid *

Dodecyl4-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)phenyl)-4-oxobutyrate*

N-((1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-N-(2-hydroxyethyl)benzamide*

TABLE B Tumor Cell Culture Cytotoxicity Data for Fully AromaticBenzoquinazo- lines (3-Amino Derivatives)

Tumor Cell Culture Cytotoxicity IC₅₀ (μM) Structure R SW480^(a)Other^(b) 8-Fluoro 50 100 (D98) 7-Fluoro 30 7-Methyl 35 53 (D98); 32 (L)7-Bromo 10 56 (D98); 28 (L) 7-Iodo 10 9-Fluoro 10 10 (MCF-7); 7 (A-427)9-Chloro 3 9-Bromo 10 30 (D98); 2.5 (L) 9-Iodo 5 9-Methoxy 20 9-Methyl30 8 (L) 9-Ethoxy 20 9-Ethyl 20 9-Ethenyl 6 9-Ethynyl 20 60 (D98); 18(L) 8-Amino 100 53 (D98); 40 (L) 6-Methoxymethyl 60 74 (D98); 56 (L)7-NH₂-8-Br 20 7-NH₂-8-F 30 7-NO₂-8-F 30 20 (D98); 14 (L) 5,6-Benzo 48-F-10-NO₂ 50 6-Methyl-9-chloro 2 7-NO₂-8-Br 25 8,9-Dichloro 20 50(D98); 45 (L) 8-F-10-NH₂ 70 8-NH₂-9-Br 15 8-NO₂-9-Br 2.5 8-Br-9-SO₂NEt₂2.5 9-Br-10-NO₂ 20 9-Br-10-NH₂ 30 7-Chloro 25 60 (D98); 46 (L) 9-OH 409-NH₂ 80 9-SO₂NEt₂ 15 9-CH₂NH-4′-C₆H₄COCH₃ 0.045 0.03 (MCF-7) ^(a)SW480is a human colon adenocarcinoma; ^(b)MCF-7 is a human breastadenocarinoma; A-427 is a lung carcinoma; D98 is a human bone marrowcell line; L is a mouse fibroblast cell line

TABLE C Tumor Cell Culture Cytotoxicity Data for5,6-Dihydrobenzoquinazolines (3-Amino Derivatives)

Tumor Cell Culture Cytotoxicity IC₅₀ (μM) Structure R SW480^(a)Other^(b) 9-Fluoro 80 90 (D98); 30 (L) 9-Chloro 25 25 (L) 9-Bromo 2512.5 (L) 9-Iodo 15 20 (MCF-7); 10 (A-427); 9-Ethynyl 35 9-Methoxy 25 70(D98); 3.3 (L) 9-Ethoxy 70 58 (D98); 40 (L) 9-Methylthio 60 46 (L)9-Ethylthio 40 54 (D98); 33 (L) 9-SO₂NEt₂ 30 8-SO₂N-(Propargyl)₂ 608-Fluoro 80 8,9-Dichloro 24 10 (MCF-7); 43 (D98); 19 (L) 7,8-Benzo 30 50(D98); 14 (L) 8-NO₂-9-Br 12 8-NH₂-9-Br 15 8-Bromo-9-N,N- 7.5diethyl-sulfonamido ^(a)SW480 is a human colon adenocarcinoma ^(b)MCF-7is a human breast adenocarcinoma; D98 is a human bone marrow cell line;L is a mouse fibroblast cell line; A-427 is a lung carcinoma.

TABLE D Tumor Cell Culture Cytotoxicity Data for5,6-Dihydrobenzoquinazolines (3-Methyl Derivatives)

Tumor Cell Culture Cytotoxicity IC₅₀ (μM) Structure R SW480^(a)Other^(b) 9-Br 65 9-I 25 70 (D98); 80 (L) 9-SO₂NH-4′-C₆H₄NO₂ 309-SO₂NH-4′-C₆H₄COCH₃ 8 9-SO₂NH-4′-C₆H₄F 25 9-SO₂NH-4′-C₆H₄CONH₂ 80 7-Br50 7-I 80 45 (D98); 50 (L) 8-NO₂ 100 52 (D98); 52 (L) 8-Br 65 ^(a)SW480is a human colon adenocarcinoma ^(b)D98 is a human bone marrow cellline; L is a mouse fibroblast cell line

TABLE E Tumor Cell Culture Cytotoxicity Data for Fully AromaticBenzoquinazo- lines (3-Methyl Derivatives)

Tumor Cell Culture Cytotoxicity IC₅₀ (μM) Structure R SW480^(a)Other^(b) 9-F 100 72 (D98); 50 (L) 9-Cl 10 82 (D98); 80 (L) 9-Br 6 68(L) 7-Cl 50 50 (D98); 84 (L) 7-Br 50 7-I 50 8-F 15 68 (D98) 8-Br 309-CH₂NH-4′-C₆H₄NO₂ 0.4 9-CH₂NH-4′-C₆H₄CN 0.03 9-CH₂NH-C₆H₅ 7.09-CH₂NH-4′-C₆H₄OMe n.a. 9-CH₂NH-3′-C₆H₄Cl n.a. 9-CH₂NH-2′C₆H₄F n.a.9-CH₂NH-3′,4′-C₆H₃F₂ n.a. 9-CH₂NH-5-(1-oxoindanyl) 0.015 0.25 (D98);0.058 (L) 9-CH₂NH-4′-C₆H₄CO₂H 2.2 9-O-4′-C₆H₄CN >109-CH₂NH-4′-C₆H₄CO(CH₂)₂CO₂H 0.7 13.5 (D98); 8.8 (L) 9-CH₂NH-4′- 0.03C₆H₄COCH₂CH(CO₂H)(CH₂)₂CO₂H 9-CH₂NH-4′-C₆H₄CO₂-n-C₁₂H₂₅ 0.49-CH₂NH-4′-C₆H₄CONH(CH₂)₂OH n.a. 9-CH₂NH-2′,5′-thienyl- 0.1CONHCH(CO₂H)(CH₂)₂CO₂H ^(a)SW480 is a human colon adenocarcinoma^(b)MCF-7 is a human breast adenocarcinoma; D98 is a human bone marrowcell line; L is a mouse fibroblast cell line

TABLE F Cell Culture Cytotoxicity (CCCT) Data for Fully AromaticBenzoquinazoline p-Aminobenzoylglutamates.

CCCT (μM) R X Other SW-480 MCF-7 NH₂ 0-CH₂NH 0.60 0.025 NH₂7-pABAglu^(a)  n.a.^(b) 8 NH₂ 9-NHSO₂ >100 n.a. NH₂ 8-SO₂NH 9-Br >50 >50CH₃ 7-SO₂NH .100 50 CH₃ 9-SO₂NH 2.4 0.07 CH₃ 9-CH₂NH 0.35 0.0075 CH₃9-CH₂NMe 1.5 0.018 CH₃ 9-CH₂NH 2′-F 0.02 0.0007 CH₃ 9-CH₂NH2′-CH₂Nglu^(c) 0.0008 0.0002 CH₃ 9-CH₂NH 2′-SNglu^(d) 2.0 n.a. CH₃9-CH₂O 70 7 CH₃ 9-CH₂NMe 2′-CH₂Nglu^(c) 0.5 n.a. CH₃ 8-CH₂NH >100 CH₃9-CH═CH >100 CH₃ 9-CH₂CH₂ 9.0 CH₃ 9-CONH n.a. ^(a)pABAglu =p-aminobenzoylglutamate residue attached to indicated position. ^(b)Notassayed. ^(c)Methylene bridge between 2′-position of aromatic ring andaminoacid nitrogen. ^(d)Sulfide bridge between 2′-position of aromaticring and aminoacid nitrogen.

TABLE G Cell Culture Cytotoxicity (CCCT) Data forDihydrobenzoquinazoline p-Aminobenzoylglutamates.

CCCT (μM) R X Other SW-480 MCF-7 NH₂ 9-SO₂NH 7.9 0.650 NH₂ 8-SO₂NH 25  n.a.^(a) NH₂ 8-SO₂N-propargyl >50 n.a. NH₂ 9-SO₂NH 8-Br >50 n.a. NH₂7-pABAglu^(b) >50 n.a. CH₃ 9-SO₂NH 4.0 0.650 CH₃ 9-SO₂NMe >50 n.a.^(a)Not assayed. ^(b)pABAglu = p-aminobenzoylglutamate residue attacheddirectly to indicated position.

The following examples illustrate pharmaceutical formulations accordingto the present invention:

Injectable solution A solution for intramuscular injection may beprepared by mixing:- Compound of formula (I) 9.5 parts by weightDimethyl sulphoxide 19.0 parts by weight Sorbitan monooleate 4.5 partsby weight Corn oil 67.0 parts by weight 100.0

Injectable solution Compound of formula (I) 5 parts by weightN-methyl-pyrollidone 48.3 parts by weight Tween 80 2 parts by weightSpan 80 4.7 parts by weight Miglyol 812 40 parts by weight 100.0

Tablet Compound of formula (I) 25.0 mg Lactose BP 48.5 mgMicrocrystalline Cellulose BP 10.0 mg (“Avicel pH 101”) Low-substitutedHydroxypropyl; 10.0 mg Cellulose BP (“LHPC LH-11”) Sodium StarchGlycollate BP 3.0 mg (“Explotab”) Povidone BP (“K30”) 3.0 mg MagnesiumStearate BP 0.5 mg 100.0 mg

Oral suspension Compound of formula (I) 50 mg Avicel RC 591 75 mgSucrose syrup 3.5 ml Methylhydroxybenzoate 5 mg Colour 0.01% w/v Cherryflavour 0.1% v/v Tween 80 0.2% v/v Water to 5 ml

Injectable suspension Compound of formula (I) 100 mg Polyvinylpyrrolidone (PVP) 170 mg Tween 80 0.2% v/v Methylhydroxybenzoate 0.1%w/v Water for Injection to 3 ml

Capsule Compound of formula (I) 100 mg Starch 1500 150 mg Magnesiumstearate 2.5 mg filled into a hard gelatin capsule

Suspension for Nebulisation Compound of formula (I), sterile 1.0 mgWater for Injections to 10.0 ml

Disperse the compound of formula (I) in the Water for Injectionspreviously sterilised in a sterile container. Fill in to sterile glassampoules, 10 ml/ampoule under aseptic conditions, and seal each ampouleby fusion of the glass.

Aerosol Formulation Compound of formula (I), micronised 1.0 mg Aerosolpropellant to 5.0 ml

Suspend the micronised compound of Formula (I) in the aerosolpropellant. Fill this suspension into preformed aerosol cannisters, 5ml/cannister under pressure, through the valve orifice.

Powder Inhalation Compound of formula (I), micronised 1.0 mg Lactose29.0 mg

Triturate and blend the micronised compound of formula (I) with thelactose. Fill the resulting powder blend into hard gelatin capsuleshells, 30 mg per capsule.

Nasal Drops Compound of formula (I) 100.0 mg Methylhydroxybenzoate 10.0mg Water for Injections to 10.0 ml

Disperse the compound of formula (I) and the methylhydroxybenzoate inthe Water for Injections. Fill this suspension into suitable dropperbottles, 10 ml/bottle, and close by securing the dropper nozzle andbottle cap.

We claim:
 1. A method for the treatment of a carcinoma in a mammal,wherein the carcinoma is a colon, breast or lung carcinoma, comprising:administering to said mammal a pharmaceutically effective amount of acompound of formula (I),

or a salt thereof, wherein the dotted line represents a single or doublebond, R¹ is C₁₋₄ alkyl or amino optionally substituted by a C₁₋₄ alkyl,C₁₋₅ alkanoyl or benzyl group; R², R³, R⁴ and R⁵ are the same ordifferent and each is selected from hydrogen, phenyl, halo, nitro, or agroup S(O)_(n)R⁸ wherein n is the integer 0, 1 or 2 and R⁸ is halo, C₁₋₄alkyl, a group NR⁹R¹⁰ wherein R⁹ and R¹⁰ are both hydrogen, a groupNR¹¹R¹² wherein R¹¹ and R¹² are the same or different and each ishydrogen or C₁₋₄ alkyl, or a group OR¹³ wherein R¹³ is hydrogen or C₁₋₄alkyl optionally substituted by halo, or a C₁₋₄ aliphatic groupoptionally substituted by a group OR¹⁴ or NR¹⁴R¹⁵ wherein R¹⁴ and R¹⁵are the same or different and each is hydrogen or C₁₋₄ alkyl; or two ofR² to R⁵ are linked together to form a benzo group, or one of R² to R⁵is a group —X—Y—R¹⁶, wherein X is CH₂, NR¹⁷, CO or S(O)_(m), m is 0, 1or 2, R¹⁷ is hydrogen or a C₁₋₄ aliphatic group, Y is CH₂, NR^(17′), O,or S(O)_(m′), m′ is 0, 1 or 2, R^(17′) is hydrogen or a C₁₋₄ aliphaticgroup provided that X and Y are only the same when each is CH₂, or —X—Y—is a group —O—, —NR¹⁷—, —CH═CH— or —N═N— wherein R¹⁷ is as hereinbeforedefined, R¹⁶ is a C₁₋₄ aliphatic group or a 5- or 6-membered aromaticring optionally substituted by a group R¹⁸ at a position at least onecarbon atom removed from that linked to Y, the 5- or 6-membered ringbeing optionally further substituted by a halo atom; R¹⁸ is halo, C₁₋₄alkoxy, nitro, nitrile, C₁₋₄ alkyl optionally substituted by halo, haloor a group COR¹⁹, R¹⁹ is hydroxy, C₁₋₄ alkoxy or C₁₋₆ alkyl optionallysubstituted by one or two carboxyl groups or C₁₋₁₂ esters thereof or agroup NR²⁰R²¹ wherein R²⁰ and R²¹ are the same or different and each ishydrogen or C₁₋₄ alkyl optionally substituted by hydroxy or a C₂₋₃alkylene group linked to the 5- or 6-membered aromatic ring to form afurther 5- or 6-membered ring, or when R¹⁸ is a C₁₋₄ alkyl groupsubstituted by COR¹⁹, R¹⁹ is an amino acid or an ester thereof in whichthe first nitrogen atom of the amino acid together with the carbons ofthe C₁₋₄ alkyl and the carbonyl carbon of COR¹⁹ may be linked to the 5-or 6-membered aromatic ring to form a further 5- or 6-memberedheterocyclic ring; R⁶ and R⁷ are the same or different and each ishydrogen, C₁₋₄ alkyl optionally substituted by hydroxy or C₁₋₄ alkoxy,or methyl substituted by bromo or together form a benzo group; providedthat at least one of R² to R⁷ is other than hydrogen or methyl and thatR⁴ is not methoxy or ethoxy when R¹ is hydroxy or methyl.
 2. A method asclaimed in claim 1, wherein R¹ is —X—Y—R¹⁶.
 3. A method as claimed inclaim 1, wherein R³ is —X—Y—R¹⁶, wherein X is CH₂, and Y is NR^(17′). 4.A method as claimed in claim 1, wherein R³ is —X—Y—R¹⁶, wherein X isCH₂, Y is NR^(17′) and R¹⁶ is a 5- or 6-membered aromatic ringoptionally substituted by a group R¹⁸ at a position at least one carbonatom removed from that linked to Y, the 5- or 6-membered ring beingoptionally further substituted by a halo atom.
 5. A method as claimed inclaim 1, wherein R³ is —X—Y—R¹⁶, wherein X is CH₂, Y is NR^(17′), R¹⁶ isa 5- or 6-membered aromatic ring optionally substituted by a group R¹⁶at a position at least one carbon atom removed from that linked to Y,the 5- or 6-membered ring being optionally further substituted by a haloatom wherein R¹⁸ is a C₁₋₄ alkyl group substituted by COR¹⁹, and R¹⁹ isan amino acid or an ester thereof in which the first nitrogen atom ofthe amino acid together with the carbons of the C₁₋₄ alkyl and thecarbonyl carbon of COR¹⁹ may be linked to the 5- or 6-membered aromaticring to form a further 5- or 6-membered heterocyclic ring.
 6. A methodas claimed in claim 5, wherein the amino acid is selected from the groupglycine, glutamic acid or polyglutamic acid.
 7. A method as claimed inclaim 5, wherein R¹⁶ is

wherein R²² is hydrogen or fluoro.
 8. A method as claimed in claim 5,wherein R¹⁶ is

wherein H₂NR^(19a) is glutamic or polyglutamic acid and Z is CH₂, S orO.
 9. A method as claimed in claim 5, wherein R¹⁶ is


10. A method as claimed in claim 1, wherein the carcinoma is a coloncarcinoma.
 11. A method as claimed in claim 1, wherein the carcinoma isa lung carcinoma.
 12. A method as claimed in claim 1, wherein thecarcinoma is a breast carcinoma.
 13. A method as claimed in claim 1,wherein the carcinoma is a colon adenocarcinoma.
 14. A method as claimedin claim 1, wherein the carcinoma is a breast adenocarcinoma.